Imaging

Posterior spinal fusion for adolescent idiopathic scoliosis is a relatively common procedure. However, intestinal obstruction is a possible complication in the case of an asthenic adolescent with weight loss after surgery. We present the case of a 12-year-old girl who underwent an uncomplicated posterior spinal fusion with instrumentation for scoliosis and who developed nausea, emesis, and abdominal pain. We also discuss the origins, epidemiology, diagnosis, and treatment of superior mesenteric artery syndrome (SMAS), a rare condition. The patient’s parents provided written informed consent for print and electronic publication of this case report.

Case Report

The patient was a 12-year-old girl with juvenile idiopathic scoliosis. She was seen by a pediatric orthopedist at age 8 after her primary care physician noticed a curve in her back during her physical examination. Given her age and primary curve of 25º, magnetic resonance imaging was ordered, which was negative for syrinx, tethered cord, or bony abnormalities. An underarm thoracolumbosacral orthosis (Boston Brace) was prescribed to be worn 23 hours/day. There was inconsistent follow-up over the next 4 years, and her curve progressed to 55º (right thoracic) and 47º in the lumbar spine (Figures 1, 2). Given the magnitude of the curves, surgical intervention was recommended, because bracing would no longer be beneficial. 

The patient was healthy and appeared vibrant with no medical issues. She weighed 49 kg and her height was 162 cm (body mass index [BMI], 18.6; normal). She underwent segmental posterior spinal instrumentation, and a fusion was performed from T4 to L4 using a cobalt chrome rod. Postoperatively, there were no problems. Her diet was slowly advanced from clear liquids to regular food over 3 days. She was discharged on postoperative day 4. She had no abdominal distention, pain, or nausea. The family was instructed about pain medication (oxycodone liquid, 5 mg every 4 hours as needed) and how to prevent and treat constipation. 

Three days after discharge, her mother called to inquire about positioning because the patient was uncomfortable owing to back pain. There were no abdominal complaints, and she was taking her pain medicine every 4 hours. She was instructed to lie in a comfortable position and to ambulate several times daily. The patient took little food or fluids because of a lack of appetite and back pain. On postoperative day 8, she presented to the emergency department with complaints of generalized abdominal pain and 1 day’s emesis. The patient had not had a bowel movement postoperatively. An acute abdominal series (AAS) was obtained (Figure 3), which noted a nonobstructive bowel gas pattern, with some increased colonic fecal retention. The patient was given intravenous (IV) fluids and an IV anti-emetic, and was admitted for observation. The pediatric surgical team evaluated her and concluded her symptoms resulted from constipation. Her symptoms improved over 2 to 3 days, and she had several bowel movements on day 2 after taking polyethylene glycol, sennosides, and bisacodyl suppositories. At discharge, she was noted to be passing gas, and her abdominal examination revealed no tenderness or guarding. She had mild distention, but it had improved from the previous day. She ate breakfast and ambulated several times. She had no complaints of abdominal pain and was released home with her parents. Staff reiterated instructions regarding constipation, diet, and follow-up. Her discharge weight was 48 kg (down 1 kg) and her BMI was 17.2 (down 1.4; underweight). Her height was now 165 cm (up 3 cm). Postoperative radiographs noted stable fixation with corrected curves (Figures 4, 5).

At home, the patient ate little but continued to drink fluids. On postdischarge day 3, she developed nausea, bilious emesis, and generalized abdominal pain. She returned to the emergency department. At this point, the patient weighed 44.5 kg (down 6.6 kg since the initial surgery) and her BMI was 16.1 (down 2.5; underweight). She was admitted, and IV fluids were initiated. She had more than 1300 mL of bilious emesis. A nasogastric (NG) tube was inserted. Initial laboratory findings were unremarkable other than an increase in serum lipase of 261 U/L. Her amylase level was within normal limits. An AAS was again completed and showed a distended stomach and loop of small bowel below the liver with an air fluid level. There were also distended loops of bowel in the pelvis (Figure 6). 

A pediatric surgical consultant examined her the next morning. An upper gastrointestinal series (UGI) was obtained and showed air fluid levels in the stomach with prompt gastric emptying into a normal caliber duodenal bulb. However, with supine positioning, there was significant dilatation of the second portion of the duodenum with abrupt vertical cutoff just to the right of the spine, compatible with SMAS (Figure 7). There was reflux of contrast material into the stomach from the duodenum, with no passage of barium into the distal duodenum. After the UGI, a nasojejunal (NJ) feeding tube was placed. The tip was left at the beginning of the fourth part of the duodenum. Repeated attempts to pass the NJ feeding tube beyond the fourth part of the duodenum were unsuccessful because of massive gastric distention. The patient was taken to the operating room for placement of a Stamm gastrostomy feeding tube with insertion of a transgastric jejunal (G-J) feeding tube under fluoroscopy (Figure 5). The patient had the G-J feeding tube in place for 6 weeks to augment her enteral nutrition. As she gained weight, her duodenal emptying improved. She gradually transitioned to normal oral intake. She has done well since the G-J feeding tube was removed. 

Discussion

Von Rokitansky first described SMAS in the mid-1800s.¹ The exact pathology was further defined 60 years later when vascular involvement was determined to be the definitive mechanism of obstruction.^2-4 Superior mesenteric artery syndrome is caused by the superior mesenteric vessels compressing the third portion of the duodenum, resulting in an extrinsic obstruction. This syndrome is also commonly called Wilkie disease, after Dr. David Wilkie, who first published in 1927 results of a comprehensive series of 75 patients.¹ The syndrome is also known as arteriomesenteric duodenal compression, aortomesenteric syndrome, chronic duodenal ileus, megaduodenum, and cast syndrome.^1,4,5 The term cast syndrome was derived from events in 1878, when Willet applied a body cast to a scoliosis patient who died after what was termed “fatal vomiting.”³

Epidemiology, Incidence, and Prevalence

While not unheard of, SMAS is an uncommon disorder. There have been only 400 documented reports in the English-language literature since 1980.^5-8 Studies have stated that the incidence of the affected population is less than 0.4%.^5,7,9,10 However, SMAS has been reported to have a mortality rate as high as 33% because of the uncommon nature of the disease and prolonged duration between onset of symptoms and diagnosis.^7,9,11,12 The incidence of SMAS is higher after surgical procedures to correct spinal deformities, with rates between 0.5% and 4.7%.^10,12,13 Females are affected more frequently than males (3:2 ratio).^1,9,14 One large study with 80 patients that spanned 10 years reported that female incidence was 66%, and another study with 75 patients also observed that two-thirds of the patients were women.^1,7 This syndrome commonly affects patients who are tall and thin with an asthenic body habitus.^1,6,11,12 Superior mesenteric artery syndrome develops more commonly in younger patients. Previous studies noted that two-thirds of patients were between ages 10 and 39 years.^1,8 However, given the right set of medical conditions, it can occur in patients of any age.^2,9,15,16 In young, thin patients with scoliosis, the risk of developing SMAS after spinal fusion with instrumentation increases, given their already low weight coupled with the surgical intervention at the height of their longitudinal growth spurt.^1,11,12 

Other patients also at increased risk for developing SMAS include those with anorexia nervosa, psychiatric/emotional disorders, or drug addiction. It can also be found in persons on prolonged bedrest, those who have increased their activity and lost weight volitionally, or patients with illness or injuries, such as burns, trauma, or significant postoperative complications that decrease caloric intake and keep them in a supine position.^2,6,17 The syndrome can be acute or chronic in its presentation.

Anatomy and Physiology

The superior mesenteric artery (SMA) comes off the right anterolateral portion of the abdominal aorta, which is just anterior to the L1 vertebra. It passes over the third part of the duodenum, generally at the L2 level (Figure 8A). The duodenum passes across the aorta at the level of the L3 vertebral body and is suspended between the aorta and the SMA by the ligament of Treitz (Figure 8B).³ The angle between the aorta and SMA (aortomesenteric angle) typically ranges from 25º to 60º with an average of 45º (Figure 8A). The distance between the aorta and SMA at the level of the duodenum is called the aortomesenteric distance, and it normally measures from 10 mm to 28 mm. Obstruction is usually observed at 2 mm to 8 mm (Figure 8C).^1,3

Compression and outlet obstruction from narrowing of the SMA aortomesenteric angle can be caused by a multitude of problems.^3,5,9,17 In chronic conditions, narrowing of the aorto-mesenteric angle could be the result of a shortened ligament, or a low origin of the SMA on the aorta, or a high insertion of the duodenum at the ligament of Treitz. Postoperatively, any change in anatomy caused by adhesions could result in compression as well. Most commonly, however, in those with significant weight loss, such as postoperative spinal fusion patients, there is loss of retroperitoneal fat, which normally acts as a cushion around the duodenum. This allows the SMA to move posteriorly obstructing the duodenum. Lying in a recumbent position along with weight loss also puts patients at risk after surgery.^3,5,9,17 SMAS should be distinguished from other conditions that can cause duodenal obstruction, such as duodenal hematomas and congenital webs. 

Symptoms and Patient Presentation

Whether SMAS is acute or chronic, most patients with SMAS present in a similar fashion. Almost all patients with acute SMAS complain of abdominal pain, nausea, and emesis (usually bilious) that usually occur after eating. Early satiety is commonly observed, resulting from delayed gastric emptying. Abdominal pain may improve when patients lie prone and are in the knee-chest, or lateral decubitus, position. These patients frequently have upper abdominal distention because of massive retention of gastric contents.^4,6,16,18,19 Most spinal fusion patients present with these symptoms 7 to 10 days after surgery.^11-13

Diagnosis

Our first diagnostic tool is a comprehensive history and physical examination. Once that is complete, many radiologic tests can be used to confirm the anatomic abnormality. The first test ordered is a simple AAS, which may show a “double bubble sign” (Figure 6), indicative of duodenal obstruction.⁴ There are several other tests, and each facility and surgeon has a preference as to which is considered the “gold standard.” Upper gastrointestinal (GI) barium studies are the simplest and most reliable. The barium test shows foregut anatomy and, to some extent, function. In SMAS patients, one should see duodenal dilatation and failure of the contrast to flow past the third section of the duodenum, along with an abrupt termination of the barium column as the duodenum crosses the vertebrae. This is the traditional method of diagnosis. There is minimal radiation, and the cost is less than that of many other tests, but it can be uncomfortable for the patient.^1-4

At some institutions, an upper GI barium study is combined with angiography, which can be used to measure aortomesenteric angle and distance.^1,3 Other practitioners prefer computed tomography (CT) with 3-dimensional reconstruction, which allows for measurement of the aortomesenteric angle and distance. In 1 study, CT was found to have an extremely high sensitivity and specificity for these measurements.¹⁰ CT angiography also identifies the obstruction with increased sensitivity, but it is rarely necessary and provides more radiation exposure and increased cost.^1,6,14,19 Abdominal ultrasound has been used to measure the angle of the SMA and the aortomesenteric distance. When combined with endoscopy, this offers an alternative way to diagnose SMAS and decreases radiation exposure. However, it may require sedation or anesthesia.^7,15,17 Overall, 3 criteria are used to define whether a patient has SMAS: duodenal dilatation, an aortomesenteric angle that is less than 25º, and an SMA that is shown to be compressing the third part of the duodenum.⁵

Treatment

Conservative treatment of SMAS usually starts by removing any precipitating factors present, such as a splint or cast that was applied for scoliosis, or ending activity associated with significant weight loss. Medical management consists of IV hydration, anti-emetics, oral feeding restriction, posture therapy, and placement of an NG tube for decompression. In most cases, patients will need to have an NJ feeding tube passed distal to the site of obstruction. This provides access for enteral feeding, and patients will gradually gain weight, repleting their retroperitoneal fat stores, which pushes the SMA forward and relieves the pressure on the duodenum. Electrolyte balance should be closely monitored along with weight gain. A nutritionist is often consulted to prevent underfeeding, which can produce a slow return to weight gain, poor wound healing, and loss of lean body muscle mass; or overfeeding, which can result in hyperglycemia and respiratory failure. Once patients are stable on enteral feedings, they can begin a slow return to oral intake.^2-4,7,12 Total parental nutrition may be needed in some cases, but the risks associated with IV feeding usually outweigh the benefits.⁴ Almost all cases of acute SMAS can be successfully treated medically if diagnosed in a timely manner and supportive treatment begins promptly.⁷

Surgical intervention is rarely necessary for acute SMAS, but when conservative measures fail (after a 4- to 6-week trial), or in the presence of peptic ulcer disease or pancreatitis, this may become an appropriate option. In our patient, multiple attempts at passing an NJ feeding tube were unsuccessful, and she needed an operative procedure for insertion of a G-J feeding tube.  

Further surgical intervention is usually reserved for those patients with long-standing SMAS for whom medical management has failed or other issues, such as pancreatitis, colitis, or megaduodenum, have arisen. Many operations are described in the literature. A duodenojejunostomy to bypass the site of the obstruction is one option. Another is duodenal derotation (Strong procedure) to alter the aortomesenteric angle and place the third and fourth duodenal portions to the right of the SMA. Other procedures include a Roux-en-Y duodenojejunostomy and duodenal uncrossing. A lateral duodenojejunostomy between the second portion of the duodenum and the jejunum is considered the simplest surgical technique. It achieves successful outcomes in 90% of cases.^2-5,14 With regards to SMAS and scoliosis, it is extremely rare that this kind of surgical intervention would be necessary.

Conclusion

When planning operative spinal correction in scoliosis patients (especially females) who have a low BMI at the time of surgery and who have increased thoracic stiffness, be alert for signs and symptoms of SMAS. This rare complication can develop, and timely diagnosis and medical management will decrease morbidity and shorten the length of time needed for nutritional rehabilitation.

Posterior spinal fusion for adolescent idiopathic scoliosis is a relatively common procedure. However, intestinal obstruction is a possible complication in the case of an asthenic adolescent with weight loss after surgery. We present the case of a 12-year-old girl who underwent an uncomplicated posterior spinal fusion with instrumentation for scoliosis and who developed nausea, emesis, and abdominal pain. We also discuss the origins, epidemiology, diagnosis, and treatment of superior mesenteric artery syndrome (SMAS), a rare condition. The patient’s parents provided written informed consent for print and electronic publication of this case report.

Case Report

The patient was a 12-year-old girl with juvenile idiopathic scoliosis. She was seen by a pediatric orthopedist at age 8 after her primary care physician noticed a curve in her back during her physical examination. Given her age and primary curve of 25º, magnetic resonance imaging was ordered, which was negative for syrinx, tethered cord, or bony abnormalities. An underarm thoracolumbosacral orthosis (Boston Brace) was prescribed to be worn 23 hours/day. There was inconsistent follow-up over the next 4 years, and her curve progressed to 55º (right thoracic) and 47º in the lumbar spine (Figures 1, 2). Given the magnitude of the curves, surgical intervention was recommended, because bracing would no longer be beneficial. 

The patient was healthy and appeared vibrant with no medical issues. She weighed 49 kg and her height was 162 cm (body mass index [BMI], 18.6; normal). She underwent segmental posterior spinal instrumentation, and a fusion was performed from T4 to L4 using a cobalt chrome rod. Postoperatively, there were no problems. Her diet was slowly advanced from clear liquids to regular food over 3 days. She was discharged on postoperative day 4. She had no abdominal distention, pain, or nausea. The family was instructed about pain medication (oxycodone liquid, 5 mg every 4 hours as needed) and how to prevent and treat constipation. 

Three days after discharge, her mother called to inquire about positioning because the patient was uncomfortable owing to back pain. There were no abdominal complaints, and she was taking her pain medicine every 4 hours. She was instructed to lie in a comfortable position and to ambulate several times daily. The patient took little food or fluids because of a lack of appetite and back pain. On postoperative day 8, she presented to the emergency department with complaints of generalized abdominal pain and 1 day’s emesis. The patient had not had a bowel movement postoperatively. An acute abdominal series (AAS) was obtained (Figure 3), which noted a nonobstructive bowel gas pattern, with some increased colonic fecal retention. The patient was given intravenous (IV) fluids and an IV anti-emetic, and was admitted for observation. The pediatric surgical team evaluated her and concluded her symptoms resulted from constipation. Her symptoms improved over 2 to 3 days, and she had several bowel movements on day 2 after taking polyethylene glycol, sennosides, and bisacodyl suppositories. At discharge, she was noted to be passing gas, and her abdominal examination revealed no tenderness or guarding. She had mild distention, but it had improved from the previous day. She ate breakfast and ambulated several times. She had no complaints of abdominal pain and was released home with her parents. Staff reiterated instructions regarding constipation, diet, and follow-up. Her discharge weight was 48 kg (down 1 kg) and her BMI was 17.2 (down 1.4; underweight). Her height was now 165 cm (up 3 cm). Postoperative radiographs noted stable fixation with corrected curves (Figures 4, 5).

At home, the patient ate little but continued to drink fluids. On postdischarge day 3, she developed nausea, bilious emesis, and generalized abdominal pain. She returned to the emergency department. At this point, the patient weighed 44.5 kg (down 6.6 kg since the initial surgery) and her BMI was 16.1 (down 2.5; underweight). She was admitted, and IV fluids were initiated. She had more than 1300 mL of bilious emesis. A nasogastric (NG) tube was inserted. Initial laboratory findings were unremarkable other than an increase in serum lipase of 261 U/L. Her amylase level was within normal limits. An AAS was again completed and showed a distended stomach and loop of small bowel below the liver with an air fluid level. There were also distended loops of bowel in the pelvis (Figure 6). 

A pediatric surgical consultant examined her the next morning. An upper gastrointestinal series (UGI) was obtained and showed air fluid levels in the stomach with prompt gastric emptying into a normal caliber duodenal bulb. However, with supine positioning, there was significant dilatation of the second portion of the duodenum with abrupt vertical cutoff just to the right of the spine, compatible with SMAS (Figure 7). There was reflux of contrast material into the stomach from the duodenum, with no passage of barium into the distal duodenum. After the UGI, a nasojejunal (NJ) feeding tube was placed. The tip was left at the beginning of the fourth part of the duodenum. Repeated attempts to pass the NJ feeding tube beyond the fourth part of the duodenum were unsuccessful because of massive gastric distention. The patient was taken to the operating room for placement of a Stamm gastrostomy feeding tube with insertion of a transgastric jejunal (G-J) feeding tube under fluoroscopy (Figure 5). The patient had the G-J feeding tube in place for 6 weeks to augment her enteral nutrition. As she gained weight, her duodenal emptying improved. She gradually transitioned to normal oral intake. She has done well since the G-J feeding tube was removed. 

Discussion

Von Rokitansky first described SMAS in the mid-1800s.¹ The exact pathology was further defined 60 years later when vascular involvement was determined to be the definitive mechanism of obstruction.^2-4 Superior mesenteric artery syndrome is caused by the superior mesenteric vessels compressing the third portion of the duodenum, resulting in an extrinsic obstruction. This syndrome is also commonly called Wilkie disease, after Dr. David Wilkie, who first published in 1927 results of a comprehensive series of 75 patients.¹ The syndrome is also known as arteriomesenteric duodenal compression, aortomesenteric syndrome, chronic duodenal ileus, megaduodenum, and cast syndrome.^1,4,5 The term cast syndrome was derived from events in 1878, when Willet applied a body cast to a scoliosis patient who died after what was termed “fatal vomiting.”³

Epidemiology, Incidence, and Prevalence

While not unheard of, SMAS is an uncommon disorder. There have been only 400 documented reports in the English-language literature since 1980.^5-8 Studies have stated that the incidence of the affected population is less than 0.4%.^5,7,9,10 However, SMAS has been reported to have a mortality rate as high as 33% because of the uncommon nature of the disease and prolonged duration between onset of symptoms and diagnosis.^7,9,11,12 The incidence of SMAS is higher after surgical procedures to correct spinal deformities, with rates between 0.5% and 4.7%.^10,12,13 Females are affected more frequently than males (3:2 ratio).^1,9,14 One large study with 80 patients that spanned 10 years reported that female incidence was 66%, and another study with 75 patients also observed that two-thirds of the patients were women.^1,7 This syndrome commonly affects patients who are tall and thin with an asthenic body habitus.^1,6,11,12 Superior mesenteric artery syndrome develops more commonly in younger patients. Previous studies noted that two-thirds of patients were between ages 10 and 39 years.^1,8 However, given the right set of medical conditions, it can occur in patients of any age.^2,9,15,16 In young, thin patients with scoliosis, the risk of developing SMAS after spinal fusion with instrumentation increases, given their already low weight coupled with the surgical intervention at the height of their longitudinal growth spurt.^1,11,12 

Other patients also at increased risk for developing SMAS include those with anorexia nervosa, psychiatric/emotional disorders, or drug addiction. It can also be found in persons on prolonged bedrest, those who have increased their activity and lost weight volitionally, or patients with illness or injuries, such as burns, trauma, or significant postoperative complications that decrease caloric intake and keep them in a supine position.^2,6,17 The syndrome can be acute or chronic in its presentation.

Anatomy and Physiology

The superior mesenteric artery (SMA) comes off the right anterolateral portion of the abdominal aorta, which is just anterior to the L1 vertebra. It passes over the third part of the duodenum, generally at the L2 level (Figure 8A). The duodenum passes across the aorta at the level of the L3 vertebral body and is suspended between the aorta and the SMA by the ligament of Treitz (Figure 8B).³ The angle between the aorta and SMA (aortomesenteric angle) typically ranges from 25º to 60º with an average of 45º (Figure 8A). The distance between the aorta and SMA at the level of the duodenum is called the aortomesenteric distance, and it normally measures from 10 mm to 28 mm. Obstruction is usually observed at 2 mm to 8 mm (Figure 8C).^1,3

Compression and outlet obstruction from narrowing of the SMA aortomesenteric angle can be caused by a multitude of problems.^3,5,9,17 In chronic conditions, narrowing of the aorto-mesenteric angle could be the result of a shortened ligament, or a low origin of the SMA on the aorta, or a high insertion of the duodenum at the ligament of Treitz. Postoperatively, any change in anatomy caused by adhesions could result in compression as well. Most commonly, however, in those with significant weight loss, such as postoperative spinal fusion patients, there is loss of retroperitoneal fat, which normally acts as a cushion around the duodenum. This allows the SMA to move posteriorly obstructing the duodenum. Lying in a recumbent position along with weight loss also puts patients at risk after surgery.^3,5,9,17 SMAS should be distinguished from other conditions that can cause duodenal obstruction, such as duodenal hematomas and congenital webs. 

Symptoms and Patient Presentation

Whether SMAS is acute or chronic, most patients with SMAS present in a similar fashion. Almost all patients with acute SMAS complain of abdominal pain, nausea, and emesis (usually bilious) that usually occur after eating. Early satiety is commonly observed, resulting from delayed gastric emptying. Abdominal pain may improve when patients lie prone and are in the knee-chest, or lateral decubitus, position. These patients frequently have upper abdominal distention because of massive retention of gastric contents.^4,6,16,18,19 Most spinal fusion patients present with these symptoms 7 to 10 days after surgery.^11-13

Diagnosis

Our first diagnostic tool is a comprehensive history and physical examination. Once that is complete, many radiologic tests can be used to confirm the anatomic abnormality. The first test ordered is a simple AAS, which may show a “double bubble sign” (Figure 6), indicative of duodenal obstruction.⁴ There are several other tests, and each facility and surgeon has a preference as to which is considered the “gold standard.” Upper gastrointestinal (GI) barium studies are the simplest and most reliable. The barium test shows foregut anatomy and, to some extent, function. In SMAS patients, one should see duodenal dilatation and failure of the contrast to flow past the third section of the duodenum, along with an abrupt termination of the barium column as the duodenum crosses the vertebrae. This is the traditional method of diagnosis. There is minimal radiation, and the cost is less than that of many other tests, but it can be uncomfortable for the patient.^1-4

At some institutions, an upper GI barium study is combined with angiography, which can be used to measure aortomesenteric angle and distance.^1,3 Other practitioners prefer computed tomography (CT) with 3-dimensional reconstruction, which allows for measurement of the aortomesenteric angle and distance. In 1 study, CT was found to have an extremely high sensitivity and specificity for these measurements.¹⁰ CT angiography also identifies the obstruction with increased sensitivity, but it is rarely necessary and provides more radiation exposure and increased cost.^1,6,14,19 Abdominal ultrasound has been used to measure the angle of the SMA and the aortomesenteric distance. When combined with endoscopy, this offers an alternative way to diagnose SMAS and decreases radiation exposure. However, it may require sedation or anesthesia.^7,15,17 Overall, 3 criteria are used to define whether a patient has SMAS: duodenal dilatation, an aortomesenteric angle that is less than 25º, and an SMA that is shown to be compressing the third part of the duodenum.⁵

Treatment

Conservative treatment of SMAS usually starts by removing any precipitating factors present, such as a splint or cast that was applied for scoliosis, or ending activity associated with significant weight loss. Medical management consists of IV hydration, anti-emetics, oral feeding restriction, posture therapy, and placement of an NG tube for decompression. In most cases, patients will need to have an NJ feeding tube passed distal to the site of obstruction. This provides access for enteral feeding, and patients will gradually gain weight, repleting their retroperitoneal fat stores, which pushes the SMA forward and relieves the pressure on the duodenum. Electrolyte balance should be closely monitored along with weight gain. A nutritionist is often consulted to prevent underfeeding, which can produce a slow return to weight gain, poor wound healing, and loss of lean body muscle mass; or overfeeding, which can result in hyperglycemia and respiratory failure. Once patients are stable on enteral feedings, they can begin a slow return to oral intake.^2-4,7,12 Total parental nutrition may be needed in some cases, but the risks associated with IV feeding usually outweigh the benefits.⁴ Almost all cases of acute SMAS can be successfully treated medically if diagnosed in a timely manner and supportive treatment begins promptly.⁷

Surgical intervention is rarely necessary for acute SMAS, but when conservative measures fail (after a 4- to 6-week trial), or in the presence of peptic ulcer disease or pancreatitis, this may become an appropriate option. In our patient, multiple attempts at passing an NJ feeding tube were unsuccessful, and she needed an operative procedure for insertion of a G-J feeding tube.  

Further surgical intervention is usually reserved for those patients with long-standing SMAS for whom medical management has failed or other issues, such as pancreatitis, colitis, or megaduodenum, have arisen. Many operations are described in the literature. A duodenojejunostomy to bypass the site of the obstruction is one option. Another is duodenal derotation (Strong procedure) to alter the aortomesenteric angle and place the third and fourth duodenal portions to the right of the SMA. Other procedures include a Roux-en-Y duodenojejunostomy and duodenal uncrossing. A lateral duodenojejunostomy between the second portion of the duodenum and the jejunum is considered the simplest surgical technique. It achieves successful outcomes in 90% of cases.^2-5,14 With regards to SMAS and scoliosis, it is extremely rare that this kind of surgical intervention would be necessary.

Conclusion

When planning operative spinal correction in scoliosis patients (especially females) who have a low BMI at the time of surgery and who have increased thoracic stiffness, be alert for signs and symptoms of SMAS. This rare complication can develop, and timely diagnosis and medical management will decrease morbidity and shorten the length of time needed for nutritional rehabilitation.

Posterior spinal fusion for adolescent idiopathic scoliosis is a relatively common procedure. However, intestinal obstruction is a possible complication in the case of an asthenic adolescent with weight loss after surgery. We present the case of a 12-year-old girl who underwent an uncomplicated posterior spinal fusion with instrumentation for scoliosis and who developed nausea, emesis, and abdominal pain. We also discuss the origins, epidemiology, diagnosis, and treatment of superior mesenteric artery syndrome (SMAS), a rare condition. The patient’s parents provided written informed consent for print and electronic publication of this case report.

Case Report

The patient was a 12-year-old girl with juvenile idiopathic scoliosis. She was seen by a pediatric orthopedist at age 8 after her primary care physician noticed a curve in her back during her physical examination. Given her age and primary curve of 25º, magnetic resonance imaging was ordered, which was negative for syrinx, tethered cord, or bony abnormalities. An underarm thoracolumbosacral orthosis (Boston Brace) was prescribed to be worn 23 hours/day. There was inconsistent follow-up over the next 4 years, and her curve progressed to 55º (right thoracic) and 47º in the lumbar spine (Figures 1, 2). Given the magnitude of the curves, surgical intervention was recommended, because bracing would no longer be beneficial. 

The patient was healthy and appeared vibrant with no medical issues. She weighed 49 kg and her height was 162 cm (body mass index [BMI], 18.6; normal). She underwent segmental posterior spinal instrumentation, and a fusion was performed from T4 to L4 using a cobalt chrome rod. Postoperatively, there were no problems. Her diet was slowly advanced from clear liquids to regular food over 3 days. She was discharged on postoperative day 4. She had no abdominal distention, pain, or nausea. The family was instructed about pain medication (oxycodone liquid, 5 mg every 4 hours as needed) and how to prevent and treat constipation. 

Three days after discharge, her mother called to inquire about positioning because the patient was uncomfortable owing to back pain. There were no abdominal complaints, and she was taking her pain medicine every 4 hours. She was instructed to lie in a comfortable position and to ambulate several times daily. The patient took little food or fluids because of a lack of appetite and back pain. On postoperative day 8, she presented to the emergency department with complaints of generalized abdominal pain and 1 day’s emesis. The patient had not had a bowel movement postoperatively. An acute abdominal series (AAS) was obtained (Figure 3), which noted a nonobstructive bowel gas pattern, with some increased colonic fecal retention. The patient was given intravenous (IV) fluids and an IV anti-emetic, and was admitted for observation. The pediatric surgical team evaluated her and concluded her symptoms resulted from constipation. Her symptoms improved over 2 to 3 days, and she had several bowel movements on day 2 after taking polyethylene glycol, sennosides, and bisacodyl suppositories. At discharge, she was noted to be passing gas, and her abdominal examination revealed no tenderness or guarding. She had mild distention, but it had improved from the previous day. She ate breakfast and ambulated several times. She had no complaints of abdominal pain and was released home with her parents. Staff reiterated instructions regarding constipation, diet, and follow-up. Her discharge weight was 48 kg (down 1 kg) and her BMI was 17.2 (down 1.4; underweight). Her height was now 165 cm (up 3 cm). Postoperative radiographs noted stable fixation with corrected curves (Figures 4, 5).

At home, the patient ate little but continued to drink fluids. On postdischarge day 3, she developed nausea, bilious emesis, and generalized abdominal pain. She returned to the emergency department. At this point, the patient weighed 44.5 kg (down 6.6 kg since the initial surgery) and her BMI was 16.1 (down 2.5; underweight). She was admitted, and IV fluids were initiated. She had more than 1300 mL of bilious emesis. A nasogastric (NG) tube was inserted. Initial laboratory findings were unremarkable other than an increase in serum lipase of 261 U/L. Her amylase level was within normal limits. An AAS was again completed and showed a distended stomach and loop of small bowel below the liver with an air fluid level. There were also distended loops of bowel in the pelvis (Figure 6). 

A pediatric surgical consultant examined her the next morning. An upper gastrointestinal series (UGI) was obtained and showed air fluid levels in the stomach with prompt gastric emptying into a normal caliber duodenal bulb. However, with supine positioning, there was significant dilatation of the second portion of the duodenum with abrupt vertical cutoff just to the right of the spine, compatible with SMAS (Figure 7). There was reflux of contrast material into the stomach from the duodenum, with no passage of barium into the distal duodenum. After the UGI, a nasojejunal (NJ) feeding tube was placed. The tip was left at the beginning of the fourth part of the duodenum. Repeated attempts to pass the NJ feeding tube beyond the fourth part of the duodenum were unsuccessful because of massive gastric distention. The patient was taken to the operating room for placement of a Stamm gastrostomy feeding tube with insertion of a transgastric jejunal (G-J) feeding tube under fluoroscopy (Figure 5). The patient had the G-J feeding tube in place for 6 weeks to augment her enteral nutrition. As she gained weight, her duodenal emptying improved. She gradually transitioned to normal oral intake. She has done well since the G-J feeding tube was removed. 

Discussion

Von Rokitansky first described SMAS in the mid-1800s.¹ The exact pathology was further defined 60 years later when vascular involvement was determined to be the definitive mechanism of obstruction.^2-4 Superior mesenteric artery syndrome is caused by the superior mesenteric vessels compressing the third portion of the duodenum, resulting in an extrinsic obstruction. This syndrome is also commonly called Wilkie disease, after Dr. David Wilkie, who first published in 1927 results of a comprehensive series of 75 patients.¹ The syndrome is also known as arteriomesenteric duodenal compression, aortomesenteric syndrome, chronic duodenal ileus, megaduodenum, and cast syndrome.^1,4,5 The term cast syndrome was derived from events in 1878, when Willet applied a body cast to a scoliosis patient who died after what was termed “fatal vomiting.”³

Epidemiology, Incidence, and Prevalence

While not unheard of, SMAS is an uncommon disorder. There have been only 400 documented reports in the English-language literature since 1980.^5-8 Studies have stated that the incidence of the affected population is less than 0.4%.^5,7,9,10 However, SMAS has been reported to have a mortality rate as high as 33% because of the uncommon nature of the disease and prolonged duration between onset of symptoms and diagnosis.^7,9,11,12 The incidence of SMAS is higher after surgical procedures to correct spinal deformities, with rates between 0.5% and 4.7%.^10,12,13 Females are affected more frequently than males (3:2 ratio).^1,9,14 One large study with 80 patients that spanned 10 years reported that female incidence was 66%, and another study with 75 patients also observed that two-thirds of the patients were women.^1,7 This syndrome commonly affects patients who are tall and thin with an asthenic body habitus.^1,6,11,12 Superior mesenteric artery syndrome develops more commonly in younger patients. Previous studies noted that two-thirds of patients were between ages 10 and 39 years.^1,8 However, given the right set of medical conditions, it can occur in patients of any age.^2,9,15,16 In young, thin patients with scoliosis, the risk of developing SMAS after spinal fusion with instrumentation increases, given their already low weight coupled with the surgical intervention at the height of their longitudinal growth spurt.^1,11,12 

Other patients also at increased risk for developing SMAS include those with anorexia nervosa, psychiatric/emotional disorders, or drug addiction. It can also be found in persons on prolonged bedrest, those who have increased their activity and lost weight volitionally, or patients with illness or injuries, such as burns, trauma, or significant postoperative complications that decrease caloric intake and keep them in a supine position.^2,6,17 The syndrome can be acute or chronic in its presentation.

Anatomy and Physiology

The superior mesenteric artery (SMA) comes off the right anterolateral portion of the abdominal aorta, which is just anterior to the L1 vertebra. It passes over the third part of the duodenum, generally at the L2 level (Figure 8A). The duodenum passes across the aorta at the level of the L3 vertebral body and is suspended between the aorta and the SMA by the ligament of Treitz (Figure 8B).³ The angle between the aorta and SMA (aortomesenteric angle) typically ranges from 25º to 60º with an average of 45º (Figure 8A). The distance between the aorta and SMA at the level of the duodenum is called the aortomesenteric distance, and it normally measures from 10 mm to 28 mm. Obstruction is usually observed at 2 mm to 8 mm (Figure 8C).^1,3

Compression and outlet obstruction from narrowing of the SMA aortomesenteric angle can be caused by a multitude of problems.^3,5,9,17 In chronic conditions, narrowing of the aorto-mesenteric angle could be the result of a shortened ligament, or a low origin of the SMA on the aorta, or a high insertion of the duodenum at the ligament of Treitz. Postoperatively, any change in anatomy caused by adhesions could result in compression as well. Most commonly, however, in those with significant weight loss, such as postoperative spinal fusion patients, there is loss of retroperitoneal fat, which normally acts as a cushion around the duodenum. This allows the SMA to move posteriorly obstructing the duodenum. Lying in a recumbent position along with weight loss also puts patients at risk after surgery.^3,5,9,17 SMAS should be distinguished from other conditions that can cause duodenal obstruction, such as duodenal hematomas and congenital webs. 

Symptoms and Patient Presentation

Whether SMAS is acute or chronic, most patients with SMAS present in a similar fashion. Almost all patients with acute SMAS complain of abdominal pain, nausea, and emesis (usually bilious) that usually occur after eating. Early satiety is commonly observed, resulting from delayed gastric emptying. Abdominal pain may improve when patients lie prone and are in the knee-chest, or lateral decubitus, position. These patients frequently have upper abdominal distention because of massive retention of gastric contents.^4,6,16,18,19 Most spinal fusion patients present with these symptoms 7 to 10 days after surgery.^11-13

Diagnosis

Our first diagnostic tool is a comprehensive history and physical examination. Once that is complete, many radiologic tests can be used to confirm the anatomic abnormality. The first test ordered is a simple AAS, which may show a “double bubble sign” (Figure 6), indicative of duodenal obstruction.⁴ There are several other tests, and each facility and surgeon has a preference as to which is considered the “gold standard.” Upper gastrointestinal (GI) barium studies are the simplest and most reliable. The barium test shows foregut anatomy and, to some extent, function. In SMAS patients, one should see duodenal dilatation and failure of the contrast to flow past the third section of the duodenum, along with an abrupt termination of the barium column as the duodenum crosses the vertebrae. This is the traditional method of diagnosis. There is minimal radiation, and the cost is less than that of many other tests, but it can be uncomfortable for the patient.^1-4

At some institutions, an upper GI barium study is combined with angiography, which can be used to measure aortomesenteric angle and distance.^1,3 Other practitioners prefer computed tomography (CT) with 3-dimensional reconstruction, which allows for measurement of the aortomesenteric angle and distance. In 1 study, CT was found to have an extremely high sensitivity and specificity for these measurements.¹⁰ CT angiography also identifies the obstruction with increased sensitivity, but it is rarely necessary and provides more radiation exposure and increased cost.^1,6,14,19 Abdominal ultrasound has been used to measure the angle of the SMA and the aortomesenteric distance. When combined with endoscopy, this offers an alternative way to diagnose SMAS and decreases radiation exposure. However, it may require sedation or anesthesia.^7,15,17 Overall, 3 criteria are used to define whether a patient has SMAS: duodenal dilatation, an aortomesenteric angle that is less than 25º, and an SMA that is shown to be compressing the third part of the duodenum.⁵

Treatment

Conservative treatment of SMAS usually starts by removing any precipitating factors present, such as a splint or cast that was applied for scoliosis, or ending activity associated with significant weight loss. Medical management consists of IV hydration, anti-emetics, oral feeding restriction, posture therapy, and placement of an NG tube for decompression. In most cases, patients will need to have an NJ feeding tube passed distal to the site of obstruction. This provides access for enteral feeding, and patients will gradually gain weight, repleting their retroperitoneal fat stores, which pushes the SMA forward and relieves the pressure on the duodenum. Electrolyte balance should be closely monitored along with weight gain. A nutritionist is often consulted to prevent underfeeding, which can produce a slow return to weight gain, poor wound healing, and loss of lean body muscle mass; or overfeeding, which can result in hyperglycemia and respiratory failure. Once patients are stable on enteral feedings, they can begin a slow return to oral intake.^2-4,7,12 Total parental nutrition may be needed in some cases, but the risks associated with IV feeding usually outweigh the benefits.⁴ Almost all cases of acute SMAS can be successfully treated medically if diagnosed in a timely manner and supportive treatment begins promptly.⁷

Surgical intervention is rarely necessary for acute SMAS, but when conservative measures fail (after a 4- to 6-week trial), or in the presence of peptic ulcer disease or pancreatitis, this may become an appropriate option. In our patient, multiple attempts at passing an NJ feeding tube were unsuccessful, and she needed an operative procedure for insertion of a G-J feeding tube.  

Further surgical intervention is usually reserved for those patients with long-standing SMAS for whom medical management has failed or other issues, such as pancreatitis, colitis, or megaduodenum, have arisen. Many operations are described in the literature. A duodenojejunostomy to bypass the site of the obstruction is one option. Another is duodenal derotation (Strong procedure) to alter the aortomesenteric angle and place the third and fourth duodenal portions to the right of the SMA. Other procedures include a Roux-en-Y duodenojejunostomy and duodenal uncrossing. A lateral duodenojejunostomy between the second portion of the duodenum and the jejunum is considered the simplest surgical technique. It achieves successful outcomes in 90% of cases.^2-5,14 With regards to SMAS and scoliosis, it is extremely rare that this kind of surgical intervention would be necessary.

Conclusion

When planning operative spinal correction in scoliosis patients (especially females) who have a low BMI at the time of surgery and who have increased thoracic stiffness, be alert for signs and symptoms of SMAS. This rare complication can develop, and timely diagnosis and medical management will decrease morbidity and shorten the length of time needed for nutritional rehabilitation.

Ollier disease, or multiple enchondromatosis, is a rare nonfamilial condition characterized by multiple cartilaginous tumors often beginning in early childhood. There is significant variation in disease distribution, location, size, number of lesions, and behavior, but the tumors are often located unilaterally.¹ Enchondromas are most commonly found in the metacarpals, metatarsals, and phalanges, and develop from metaphyseal bone in close proximity to the physis. They frequently present as painless masses or are incidentally noted during the evaluation of another musculoskeletal condition. Radiographically, enchondromas of the hands and feet appear as oval radiolucencies with thinned, sclerotic rims. The lesions have varying degrees of mineralization and endosteal scalloping, and may expand the bone.² Enchondromas usually enlarge until skeletal maturity and have been observed to ossify spontaneously.^1,3 The clinical course of Ollier disease is variable, and a number of cases of significant hand deformity and malignant transformation have been reported.^4-6

In this case report, we present a mild form of Ollier disease isolated to the patient’s left hand, which we followed for 8 years, demonstrating part of the natural history of these lesions. We discuss the patient’s clinical features, radiologic findings, diagnosis, treatment, prognosis, and follow-up, as well as review the literature. The patient and the patient’s family provided written informed consent for print and electronic publication of this case report.

Case Report

A 10-year-old, right-handed girl was referred to our department for the evaluation of left-hand masses. At age 3 years, the patient underwent a chondroma excision from the middle phalanx of her middle finger on her left hand. No operative or pathology report was available from this surgery, and the patient tolerated the procedure well without any complications. At the time of presentation, the masses did not cause any pain, motor or sensory dysfunction, or any systemic symptoms. No history of recent or distant trauma was elicited. The patient’s medical and family history was unremarkable.

On physical examination, there was a firm, immobile, nontender palpable mass over the dorsal aspect of the distal second metacarpal bone of the left hand. The mass extended medially between the second and third metacarpals. A second small, firm, nontender left-hand mass was palpated over the volar aspect of her proximal phalanx on her index finger. She was neurovascularly intact with full active range of motion of the metacarpophalangeal and proximal and distal interphalangeal joints. There was no angular deformity of the digits. Plain radiographs taken at the time of initial presentation showed a 2.3×1.7-cm radiolucent lesion located in the metaphysis and diaphysis of the second metacarpal of the left hand (Figures 1A-1C). The lesion had varying degrees of mineralization with cortical thinning and expansion in the volar, dorsal, radial, and ulnar directions, consistent with a chondroid lesion. The second and third lesions were oval radiolucencies with sclerotic rims located at the metaphyseal-diaphyseal junction of the proximal phalanx of the index finger and middle phalanx of the middle finger, respectively. No fractures were identified in the radiographs, and the physes were open at this time. The patient was diagnosed with multiple enchondromatosis, or Ollier disease.

Our case showed 1 episode of pain and tenderness to palpation at the second proximal phalanx approximately 6 months after initial presentation. We attributed the pain and tenderness to a small pathologic fracture but did not see radiographic evidence of this. We elected to provide a trial of supportive measures, such as splinting and buddy taping, and to monitor the pain with a tentative plan of open biopsy with curettage and bone grafting if the pain persisted or evidence of fracture was seen on radiographs. The pain and tenderness to palpation resolved at a follow-up visit, and the surgery was deferred.

The patient was treated nonoperatively at initial presentation given the lack of significant cosmetic deformity or functional compromise and was advised close follow-up at 3 and 6 months. Given the absence of disease progression, annual checks (ie, clinical examination and radiographs) in a skeletally immature patient were decided on after consultation with the patient and parent. The family was educated about the possibility of pathologic fracture from minimal trauma to the hand versus the small risk of iatrogenic physeal injury with surgical curettage and bone grafting. No protective splinting was offered. A favorable prognosis and reassurance was provided to the patient and family, given the absence of symptoms, low suspicion and risk of malignant transformation, and stability of the lesion. Serial radiographs showed gradual increases in the lesions’ sizes but were consistent with the stable growth of the metacarpal and phalanges. With the patient nearing skeletal maturity, no pathologic fractures were identified on radiography during follow-up, and the risks of surgery lessened with growth; however, the continued absence of symptoms led to the mutual decision to continue observation.

Nearly 8 years after initial presentation, plain radiographs showed closed physes and partially ossified bone masses (Figures 2A-2C). The metacarpal lesion measured 3.2×1.5 cm, and the cortex appeared thickened and regular. The proximal phalanx lesion had a thickened cortex without periosteal reaction, and the middle phalanx lesion appeared to be completely healed. The patient has been asymptomatic for many years, and she has retained complete function of her left hand without any growth retardation, angular deformity, or pathologic fracture. A small but potential risk of malignant transformation was discussed with the patient and her family, as was the need for lifetime follow-up. We intend to follow the enchondromas clinically and radiographically every 2 years and obtain new radiographs if the mass presents with new clinical findings, such as enlargement or pain, for surveillance of tumor transformation. If the patient desired or symptoms developed, curettage and bone grafting would be offered, and the surgical tissue would be sent for pathologic analysis. A bone scan that was obtained at the request of the patient, when she was 21 years old, showed no other sites of disease besides the fingers.

Discussion

Multiple enchondromatosis was first described by Ollier at the turn of the 19th century and has been estimated to affect one in every 100,000 persons.¹ The low prevalence and variable manifestations of Ollier disease lead clinicians to handle the disease and its complications, namely skeletal deformity and malignant transformation, on a case-by-case approach. Additionally, the prognosis of Ollier disease with malignant transformation is quite variable, with studies reporting the estimated incidence as 5% to 50%.⁷ Muramatsu and colleagues⁶ reported that the occurrence of malignant transformation of multiple enchondromas limited to the bones of the hand was extremely rare, with only 12 cases of malignant transformation. Enchondromas of the pelvis, scapula, and long bones of the extremities have increased risks and rates of secondary transformation to chondrosarcoma.⁸

A recent large European multicenter retrospective study investigating the clinical characteristics and behavior of enchondromas in 144 patients with Ollier disease has provided new information regarding this rare disease.⁷ Verdegaal and colleagues⁷ divided patients into 3 categories depending on their distribution of enchondromas. The development of chondrosarcoma was notably different between individuals with enchondromas limited to the small bones of the hands and feet (15%, group I) versus individuals with enchondromas limited to the long bones and flat bones (43%, group II) or individuals with enchondromas of the short, long, and flat bones (46%, group III).⁷ The only location found to be statistically significant for the development of chondrosarcoma was the pelvis.

The clinical findings associated with risk of malignant transformation of enchondromas are increasing size of the lesion and onset of pain and tenderness. Dahlin and Salvador⁹ reported that only 60% of patients with chondrosarcoma of the hand experience pain. The absence of pain may lead to a delay in patient presentation to the clinician.^5,6 Radiographic findings of malignant transformation include the classic features of temporal increases in the lesion’s size after skeletal maturity and cortical destruction associated with soft-tissue invasion. However, both findings are nonspecific for differentiating enchondromas from grade 1 chondrosarcomas as described by Geirnaerdt and colleagues.¹⁰

Sassoon and colleagues¹¹ reported on a series of hand enchondromas treated operatively. Subgroup analysis between pathologic fractures treated primarily or in delayed fashion showed similar outcomes for achieving full motion and similar number of complications; however, they noted that the delayed group required 7 more weeks of immobilization. Additionally, review of the whole series showed 1 episode of metacarpal shortening and 1 occurrence of angular malalignment. In our patient, we were concerned about introducing an iatrogenic cosmetic deformity, and we believed a pathologic fracture could be managed expectantly. Overall, patients without pathologic fracture treated surgically experienced a complication rate of 12%, whereas patients with a fracture had a complication rate of 20%.¹¹ The majority of patients with multiple enchondromatosis treated with surgical curettage and grafting had successful outcomes, with 86% of patients regaining full motion, but the recurrence rate was 21%.¹¹ Patients with expansile lesions regained less motion than patients with nonexpansile lesions. There was a single lesion believed preoperatively to be an enchondroma, but it underwent malignant transformation, as confirmed on intraoperative pathology. This patient had Maffucci syndrome and was treated with an amputation through the metacarpophalangeal joint.

There are 3 options for treating hand enchondromas: observation, curettage alone, or curettage with bone grafting. There is no consensus about conservative management, timing of intervention, or risk of pathologic fracture. Each patient is treated individually with attention to reason for presentation, number of lesions, associated pain, deformity, or pathologic fracture. Operative criteria include high risk of pathologic fracture based on location of enchondroma, cortical thinning, and previous pathologic fracture with resulting angular deformity. Nonoperative management may increase the risk of pathologic fracture, particularly in patients involved in aggressive contact sports, but the physician may offer protective splinting or counsel the patient on activity modification. Our case provides a study of the natural history of multiple enchondromatosis and shows mild increases in the lesions’ sizes during the 8-year follow-up. This was an expected finding given the patient’s immature skeleton. The lesions’ cortices continued to ossify after the physes closed and now provides an excellent comparison for the identification of future malignant changes. 

Histologic analysis of biopsied or surgically treated lesions contributes to the differentiation between benign hand enchondromas and chondrosarcoma. Pathologic findings must be correlated with clinical and radiographic findings because hand enchondromas contain cytologic features of chondrosarcoma.¹² In a series of 55 patients with chondrosarcoma, Liu and colleagues⁸ reported no cases from the hand. Verdegaal and colleagues⁷ reported a total of 13 chondrosarcomas in the metacarpals and hand phalanges in 97 group I and III patients. Five of these lesions were grade 1, 2 were grade 2, 1 was grade 3, and 5 lesions were unknown.

For patients with multiple enchondromatosis limited to the hands, prognosis is relatively good with respect to risk of secondary chondrosarcoma transformation, metastasis of secondary chondrosarcoma, and death. Verdegaal and colleagues⁷ reported the rate of secondary transformation in the hand to be 15%. Patil and colleagues¹³ reported no distant metastases in 23 patients with hand chondrosarcoma at mean follow-up of 8.5 years (range, 2-19 years), although none of their patients had Ollier disease. Verdegaal and colleagues⁷ reported 7 of the 8 deaths in their study were related to development of pulmonary metastases; however, none originated from chondrosarcomas in the hand. Additionally, there were no disease-related deaths in 29 group I patients. Herget and colleagues,¹⁴ in summarizing the literature, postulated that the overall survival rate of patients with secondary chondrosarcoma at 5 years is approximately 90%.

In our case, the patient, who had 3 enchondromas isolated to the left hand, can be categorized in group I. Thus, this case highlights the natural history of a patient with hand enchondromas and demonstrates that enchondromatosis of the short tubular bones of the hands can mature and ossify.

Ollier disease, or multiple enchondromatosis, is a rare nonfamilial condition characterized by multiple cartilaginous tumors often beginning in early childhood. There is significant variation in disease distribution, location, size, number of lesions, and behavior, but the tumors are often located unilaterally.¹ Enchondromas are most commonly found in the metacarpals, metatarsals, and phalanges, and develop from metaphyseal bone in close proximity to the physis. They frequently present as painless masses or are incidentally noted during the evaluation of another musculoskeletal condition. Radiographically, enchondromas of the hands and feet appear as oval radiolucencies with thinned, sclerotic rims. The lesions have varying degrees of mineralization and endosteal scalloping, and may expand the bone.² Enchondromas usually enlarge until skeletal maturity and have been observed to ossify spontaneously.^1,3 The clinical course of Ollier disease is variable, and a number of cases of significant hand deformity and malignant transformation have been reported.^4-6

In this case report, we present a mild form of Ollier disease isolated to the patient’s left hand, which we followed for 8 years, demonstrating part of the natural history of these lesions. We discuss the patient’s clinical features, radiologic findings, diagnosis, treatment, prognosis, and follow-up, as well as review the literature. The patient and the patient’s family provided written informed consent for print and electronic publication of this case report.

Case Report

A 10-year-old, right-handed girl was referred to our department for the evaluation of left-hand masses. At age 3 years, the patient underwent a chondroma excision from the middle phalanx of her middle finger on her left hand. No operative or pathology report was available from this surgery, and the patient tolerated the procedure well without any complications. At the time of presentation, the masses did not cause any pain, motor or sensory dysfunction, or any systemic symptoms. No history of recent or distant trauma was elicited. The patient’s medical and family history was unremarkable.

On physical examination, there was a firm, immobile, nontender palpable mass over the dorsal aspect of the distal second metacarpal bone of the left hand. The mass extended medially between the second and third metacarpals. A second small, firm, nontender left-hand mass was palpated over the volar aspect of her proximal phalanx on her index finger. She was neurovascularly intact with full active range of motion of the metacarpophalangeal and proximal and distal interphalangeal joints. There was no angular deformity of the digits. Plain radiographs taken at the time of initial presentation showed a 2.3×1.7-cm radiolucent lesion located in the metaphysis and diaphysis of the second metacarpal of the left hand (Figures 1A-1C). The lesion had varying degrees of mineralization with cortical thinning and expansion in the volar, dorsal, radial, and ulnar directions, consistent with a chondroid lesion. The second and third lesions were oval radiolucencies with sclerotic rims located at the metaphyseal-diaphyseal junction of the proximal phalanx of the index finger and middle phalanx of the middle finger, respectively. No fractures were identified in the radiographs, and the physes were open at this time. The patient was diagnosed with multiple enchondromatosis, or Ollier disease.

Our case showed 1 episode of pain and tenderness to palpation at the second proximal phalanx approximately 6 months after initial presentation. We attributed the pain and tenderness to a small pathologic fracture but did not see radiographic evidence of this. We elected to provide a trial of supportive measures, such as splinting and buddy taping, and to monitor the pain with a tentative plan of open biopsy with curettage and bone grafting if the pain persisted or evidence of fracture was seen on radiographs. The pain and tenderness to palpation resolved at a follow-up visit, and the surgery was deferred.

The patient was treated nonoperatively at initial presentation given the lack of significant cosmetic deformity or functional compromise and was advised close follow-up at 3 and 6 months. Given the absence of disease progression, annual checks (ie, clinical examination and radiographs) in a skeletally immature patient were decided on after consultation with the patient and parent. The family was educated about the possibility of pathologic fracture from minimal trauma to the hand versus the small risk of iatrogenic physeal injury with surgical curettage and bone grafting. No protective splinting was offered. A favorable prognosis and reassurance was provided to the patient and family, given the absence of symptoms, low suspicion and risk of malignant transformation, and stability of the lesion. Serial radiographs showed gradual increases in the lesions’ sizes but were consistent with the stable growth of the metacarpal and phalanges. With the patient nearing skeletal maturity, no pathologic fractures were identified on radiography during follow-up, and the risks of surgery lessened with growth; however, the continued absence of symptoms led to the mutual decision to continue observation.

Nearly 8 years after initial presentation, plain radiographs showed closed physes and partially ossified bone masses (Figures 2A-2C). The metacarpal lesion measured 3.2×1.5 cm, and the cortex appeared thickened and regular. The proximal phalanx lesion had a thickened cortex without periosteal reaction, and the middle phalanx lesion appeared to be completely healed. The patient has been asymptomatic for many years, and she has retained complete function of her left hand without any growth retardation, angular deformity, or pathologic fracture. A small but potential risk of malignant transformation was discussed with the patient and her family, as was the need for lifetime follow-up. We intend to follow the enchondromas clinically and radiographically every 2 years and obtain new radiographs if the mass presents with new clinical findings, such as enlargement or pain, for surveillance of tumor transformation. If the patient desired or symptoms developed, curettage and bone grafting would be offered, and the surgical tissue would be sent for pathologic analysis. A bone scan that was obtained at the request of the patient, when she was 21 years old, showed no other sites of disease besides the fingers.

Discussion

Multiple enchondromatosis was first described by Ollier at the turn of the 19th century and has been estimated to affect one in every 100,000 persons.¹ The low prevalence and variable manifestations of Ollier disease lead clinicians to handle the disease and its complications, namely skeletal deformity and malignant transformation, on a case-by-case approach. Additionally, the prognosis of Ollier disease with malignant transformation is quite variable, with studies reporting the estimated incidence as 5% to 50%.⁷ Muramatsu and colleagues⁶ reported that the occurrence of malignant transformation of multiple enchondromas limited to the bones of the hand was extremely rare, with only 12 cases of malignant transformation. Enchondromas of the pelvis, scapula, and long bones of the extremities have increased risks and rates of secondary transformation to chondrosarcoma.⁸

A recent large European multicenter retrospective study investigating the clinical characteristics and behavior of enchondromas in 144 patients with Ollier disease has provided new information regarding this rare disease.⁷ Verdegaal and colleagues⁷ divided patients into 3 categories depending on their distribution of enchondromas. The development of chondrosarcoma was notably different between individuals with enchondromas limited to the small bones of the hands and feet (15%, group I) versus individuals with enchondromas limited to the long bones and flat bones (43%, group II) or individuals with enchondromas of the short, long, and flat bones (46%, group III).⁷ The only location found to be statistically significant for the development of chondrosarcoma was the pelvis.

The clinical findings associated with risk of malignant transformation of enchondromas are increasing size of the lesion and onset of pain and tenderness. Dahlin and Salvador⁹ reported that only 60% of patients with chondrosarcoma of the hand experience pain. The absence of pain may lead to a delay in patient presentation to the clinician.^5,6 Radiographic findings of malignant transformation include the classic features of temporal increases in the lesion’s size after skeletal maturity and cortical destruction associated with soft-tissue invasion. However, both findings are nonspecific for differentiating enchondromas from grade 1 chondrosarcomas as described by Geirnaerdt and colleagues.¹⁰

Sassoon and colleagues¹¹ reported on a series of hand enchondromas treated operatively. Subgroup analysis between pathologic fractures treated primarily or in delayed fashion showed similar outcomes for achieving full motion and similar number of complications; however, they noted that the delayed group required 7 more weeks of immobilization. Additionally, review of the whole series showed 1 episode of metacarpal shortening and 1 occurrence of angular malalignment. In our patient, we were concerned about introducing an iatrogenic cosmetic deformity, and we believed a pathologic fracture could be managed expectantly. Overall, patients without pathologic fracture treated surgically experienced a complication rate of 12%, whereas patients with a fracture had a complication rate of 20%.¹¹ The majority of patients with multiple enchondromatosis treated with surgical curettage and grafting had successful outcomes, with 86% of patients regaining full motion, but the recurrence rate was 21%.¹¹ Patients with expansile lesions regained less motion than patients with nonexpansile lesions. There was a single lesion believed preoperatively to be an enchondroma, but it underwent malignant transformation, as confirmed on intraoperative pathology. This patient had Maffucci syndrome and was treated with an amputation through the metacarpophalangeal joint.

There are 3 options for treating hand enchondromas: observation, curettage alone, or curettage with bone grafting. There is no consensus about conservative management, timing of intervention, or risk of pathologic fracture. Each patient is treated individually with attention to reason for presentation, number of lesions, associated pain, deformity, or pathologic fracture. Operative criteria include high risk of pathologic fracture based on location of enchondroma, cortical thinning, and previous pathologic fracture with resulting angular deformity. Nonoperative management may increase the risk of pathologic fracture, particularly in patients involved in aggressive contact sports, but the physician may offer protective splinting or counsel the patient on activity modification. Our case provides a study of the natural history of multiple enchondromatosis and shows mild increases in the lesions’ sizes during the 8-year follow-up. This was an expected finding given the patient’s immature skeleton. The lesions’ cortices continued to ossify after the physes closed and now provides an excellent comparison for the identification of future malignant changes. 

Histologic analysis of biopsied or surgically treated lesions contributes to the differentiation between benign hand enchondromas and chondrosarcoma. Pathologic findings must be correlated with clinical and radiographic findings because hand enchondromas contain cytologic features of chondrosarcoma.¹² In a series of 55 patients with chondrosarcoma, Liu and colleagues⁸ reported no cases from the hand. Verdegaal and colleagues⁷ reported a total of 13 chondrosarcomas in the metacarpals and hand phalanges in 97 group I and III patients. Five of these lesions were grade 1, 2 were grade 2, 1 was grade 3, and 5 lesions were unknown.

For patients with multiple enchondromatosis limited to the hands, prognosis is relatively good with respect to risk of secondary chondrosarcoma transformation, metastasis of secondary chondrosarcoma, and death. Verdegaal and colleagues⁷ reported the rate of secondary transformation in the hand to be 15%. Patil and colleagues¹³ reported no distant metastases in 23 patients with hand chondrosarcoma at mean follow-up of 8.5 years (range, 2-19 years), although none of their patients had Ollier disease. Verdegaal and colleagues⁷ reported 7 of the 8 deaths in their study were related to development of pulmonary metastases; however, none originated from chondrosarcomas in the hand. Additionally, there were no disease-related deaths in 29 group I patients. Herget and colleagues,¹⁴ in summarizing the literature, postulated that the overall survival rate of patients with secondary chondrosarcoma at 5 years is approximately 90%.

In our case, the patient, who had 3 enchondromas isolated to the left hand, can be categorized in group I. Thus, this case highlights the natural history of a patient with hand enchondromas and demonstrates that enchondromatosis of the short tubular bones of the hands can mature and ossify.

Ollier disease, or multiple enchondromatosis, is a rare nonfamilial condition characterized by multiple cartilaginous tumors often beginning in early childhood. There is significant variation in disease distribution, location, size, number of lesions, and behavior, but the tumors are often located unilaterally.¹ Enchondromas are most commonly found in the metacarpals, metatarsals, and phalanges, and develop from metaphyseal bone in close proximity to the physis. They frequently present as painless masses or are incidentally noted during the evaluation of another musculoskeletal condition. Radiographically, enchondromas of the hands and feet appear as oval radiolucencies with thinned, sclerotic rims. The lesions have varying degrees of mineralization and endosteal scalloping, and may expand the bone.² Enchondromas usually enlarge until skeletal maturity and have been observed to ossify spontaneously.^1,3 The clinical course of Ollier disease is variable, and a number of cases of significant hand deformity and malignant transformation have been reported.^4-6

In this case report, we present a mild form of Ollier disease isolated to the patient’s left hand, which we followed for 8 years, demonstrating part of the natural history of these lesions. We discuss the patient’s clinical features, radiologic findings, diagnosis, treatment, prognosis, and follow-up, as well as review the literature. The patient and the patient’s family provided written informed consent for print and electronic publication of this case report.

Case Report

A 10-year-old, right-handed girl was referred to our department for the evaluation of left-hand masses. At age 3 years, the patient underwent a chondroma excision from the middle phalanx of her middle finger on her left hand. No operative or pathology report was available from this surgery, and the patient tolerated the procedure well without any complications. At the time of presentation, the masses did not cause any pain, motor or sensory dysfunction, or any systemic symptoms. No history of recent or distant trauma was elicited. The patient’s medical and family history was unremarkable.

On physical examination, there was a firm, immobile, nontender palpable mass over the dorsal aspect of the distal second metacarpal bone of the left hand. The mass extended medially between the second and third metacarpals. A second small, firm, nontender left-hand mass was palpated over the volar aspect of her proximal phalanx on her index finger. She was neurovascularly intact with full active range of motion of the metacarpophalangeal and proximal and distal interphalangeal joints. There was no angular deformity of the digits. Plain radiographs taken at the time of initial presentation showed a 2.3×1.7-cm radiolucent lesion located in the metaphysis and diaphysis of the second metacarpal of the left hand (Figures 1A-1C). The lesion had varying degrees of mineralization with cortical thinning and expansion in the volar, dorsal, radial, and ulnar directions, consistent with a chondroid lesion. The second and third lesions were oval radiolucencies with sclerotic rims located at the metaphyseal-diaphyseal junction of the proximal phalanx of the index finger and middle phalanx of the middle finger, respectively. No fractures were identified in the radiographs, and the physes were open at this time. The patient was diagnosed with multiple enchondromatosis, or Ollier disease.

Our case showed 1 episode of pain and tenderness to palpation at the second proximal phalanx approximately 6 months after initial presentation. We attributed the pain and tenderness to a small pathologic fracture but did not see radiographic evidence of this. We elected to provide a trial of supportive measures, such as splinting and buddy taping, and to monitor the pain with a tentative plan of open biopsy with curettage and bone grafting if the pain persisted or evidence of fracture was seen on radiographs. The pain and tenderness to palpation resolved at a follow-up visit, and the surgery was deferred.

The patient was treated nonoperatively at initial presentation given the lack of significant cosmetic deformity or functional compromise and was advised close follow-up at 3 and 6 months. Given the absence of disease progression, annual checks (ie, clinical examination and radiographs) in a skeletally immature patient were decided on after consultation with the patient and parent. The family was educated about the possibility of pathologic fracture from minimal trauma to the hand versus the small risk of iatrogenic physeal injury with surgical curettage and bone grafting. No protective splinting was offered. A favorable prognosis and reassurance was provided to the patient and family, given the absence of symptoms, low suspicion and risk of malignant transformation, and stability of the lesion. Serial radiographs showed gradual increases in the lesions’ sizes but were consistent with the stable growth of the metacarpal and phalanges. With the patient nearing skeletal maturity, no pathologic fractures were identified on radiography during follow-up, and the risks of surgery lessened with growth; however, the continued absence of symptoms led to the mutual decision to continue observation.

Nearly 8 years after initial presentation, plain radiographs showed closed physes and partially ossified bone masses (Figures 2A-2C). The metacarpal lesion measured 3.2×1.5 cm, and the cortex appeared thickened and regular. The proximal phalanx lesion had a thickened cortex without periosteal reaction, and the middle phalanx lesion appeared to be completely healed. The patient has been asymptomatic for many years, and she has retained complete function of her left hand without any growth retardation, angular deformity, or pathologic fracture. A small but potential risk of malignant transformation was discussed with the patient and her family, as was the need for lifetime follow-up. We intend to follow the enchondromas clinically and radiographically every 2 years and obtain new radiographs if the mass presents with new clinical findings, such as enlargement or pain, for surveillance of tumor transformation. If the patient desired or symptoms developed, curettage and bone grafting would be offered, and the surgical tissue would be sent for pathologic analysis. A bone scan that was obtained at the request of the patient, when she was 21 years old, showed no other sites of disease besides the fingers.

Discussion

Multiple enchondromatosis was first described by Ollier at the turn of the 19th century and has been estimated to affect one in every 100,000 persons.¹ The low prevalence and variable manifestations of Ollier disease lead clinicians to handle the disease and its complications, namely skeletal deformity and malignant transformation, on a case-by-case approach. Additionally, the prognosis of Ollier disease with malignant transformation is quite variable, with studies reporting the estimated incidence as 5% to 50%.⁷ Muramatsu and colleagues⁶ reported that the occurrence of malignant transformation of multiple enchondromas limited to the bones of the hand was extremely rare, with only 12 cases of malignant transformation. Enchondromas of the pelvis, scapula, and long bones of the extremities have increased risks and rates of secondary transformation to chondrosarcoma.⁸

A recent large European multicenter retrospective study investigating the clinical characteristics and behavior of enchondromas in 144 patients with Ollier disease has provided new information regarding this rare disease.⁷ Verdegaal and colleagues⁷ divided patients into 3 categories depending on their distribution of enchondromas. The development of chondrosarcoma was notably different between individuals with enchondromas limited to the small bones of the hands and feet (15%, group I) versus individuals with enchondromas limited to the long bones and flat bones (43%, group II) or individuals with enchondromas of the short, long, and flat bones (46%, group III).⁷ The only location found to be statistically significant for the development of chondrosarcoma was the pelvis.

The clinical findings associated with risk of malignant transformation of enchondromas are increasing size of the lesion and onset of pain and tenderness. Dahlin and Salvador⁹ reported that only 60% of patients with chondrosarcoma of the hand experience pain. The absence of pain may lead to a delay in patient presentation to the clinician.^5,6 Radiographic findings of malignant transformation include the classic features of temporal increases in the lesion’s size after skeletal maturity and cortical destruction associated with soft-tissue invasion. However, both findings are nonspecific for differentiating enchondromas from grade 1 chondrosarcomas as described by Geirnaerdt and colleagues.¹⁰

Sassoon and colleagues¹¹ reported on a series of hand enchondromas treated operatively. Subgroup analysis between pathologic fractures treated primarily or in delayed fashion showed similar outcomes for achieving full motion and similar number of complications; however, they noted that the delayed group required 7 more weeks of immobilization. Additionally, review of the whole series showed 1 episode of metacarpal shortening and 1 occurrence of angular malalignment. In our patient, we were concerned about introducing an iatrogenic cosmetic deformity, and we believed a pathologic fracture could be managed expectantly. Overall, patients without pathologic fracture treated surgically experienced a complication rate of 12%, whereas patients with a fracture had a complication rate of 20%.¹¹ The majority of patients with multiple enchondromatosis treated with surgical curettage and grafting had successful outcomes, with 86% of patients regaining full motion, but the recurrence rate was 21%.¹¹ Patients with expansile lesions regained less motion than patients with nonexpansile lesions. There was a single lesion believed preoperatively to be an enchondroma, but it underwent malignant transformation, as confirmed on intraoperative pathology. This patient had Maffucci syndrome and was treated with an amputation through the metacarpophalangeal joint.

There are 3 options for treating hand enchondromas: observation, curettage alone, or curettage with bone grafting. There is no consensus about conservative management, timing of intervention, or risk of pathologic fracture. Each patient is treated individually with attention to reason for presentation, number of lesions, associated pain, deformity, or pathologic fracture. Operative criteria include high risk of pathologic fracture based on location of enchondroma, cortical thinning, and previous pathologic fracture with resulting angular deformity. Nonoperative management may increase the risk of pathologic fracture, particularly in patients involved in aggressive contact sports, but the physician may offer protective splinting or counsel the patient on activity modification. Our case provides a study of the natural history of multiple enchondromatosis and shows mild increases in the lesions’ sizes during the 8-year follow-up. This was an expected finding given the patient’s immature skeleton. The lesions’ cortices continued to ossify after the physes closed and now provides an excellent comparison for the identification of future malignant changes. 

Histologic analysis of biopsied or surgically treated lesions contributes to the differentiation between benign hand enchondromas and chondrosarcoma. Pathologic findings must be correlated with clinical and radiographic findings because hand enchondromas contain cytologic features of chondrosarcoma.¹² In a series of 55 patients with chondrosarcoma, Liu and colleagues⁸ reported no cases from the hand. Verdegaal and colleagues⁷ reported a total of 13 chondrosarcomas in the metacarpals and hand phalanges in 97 group I and III patients. Five of these lesions were grade 1, 2 were grade 2, 1 was grade 3, and 5 lesions were unknown.

For patients with multiple enchondromatosis limited to the hands, prognosis is relatively good with respect to risk of secondary chondrosarcoma transformation, metastasis of secondary chondrosarcoma, and death. Verdegaal and colleagues⁷ reported the rate of secondary transformation in the hand to be 15%. Patil and colleagues¹³ reported no distant metastases in 23 patients with hand chondrosarcoma at mean follow-up of 8.5 years (range, 2-19 years), although none of their patients had Ollier disease. Verdegaal and colleagues⁷ reported 7 of the 8 deaths in their study were related to development of pulmonary metastases; however, none originated from chondrosarcomas in the hand. Additionally, there were no disease-related deaths in 29 group I patients. Herget and colleagues,¹⁴ in summarizing the literature, postulated that the overall survival rate of patients with secondary chondrosarcoma at 5 years is approximately 90%.

In our case, the patient, who had 3 enchondromas isolated to the left hand, can be categorized in group I. Thus, this case highlights the natural history of a patient with hand enchondromas and demonstrates that enchondromatosis of the short tubular bones of the hands can mature and ossify.

Tourniquets are often used in total knee arthroplasty (TKA) to improve visualization of structures, shorten operative time, reduce intraoperative bleeding, and improve cementing technique. Despite these advantages, controversy remains regarding the safety of tourniquet use. Tourniquets have been associated with nerve palsies, vascular injury, and muscle damage.^1-5 Some have hypothesized they may cause venous stasis or direct endothelial damage that may develop into deep vein thrombosis (DVT). Abdel-Salam and Eyres⁶ found an increased incidence of postoperative wound complications and DVTs associated with tourniquet use.

Moreover, investigators have analyzed the role of tourniquets in populations at high risk for wound complications. DeLaurentis and colleagues⁷ performed a prospective and retrospective analysis of 1182 TKA patients, 24 (2%) of whom had preexisting peripheral vascular disease (PVD), defined as a history of arterial insufficiency, absent dorsalis pedis and/or absent posterior tibial pulsations, and arterial calcifications. A tourniquet was used in each case. Arterial complications occurred in 6 of the 24 patients with PVD. As expected, the authors found that a history of intermittent claudication, pain at rest, and arterial ulcers resulted in a high risk for vascular complications. Further studies have supported this finding and expanded the list of predisposing factors to include previous vascular surgery and absent and asymmetric pedal pulsations.^7-11 Of particular concern to total joint arthroplasty surgeons was the finding by DeLaurentis and colleagues⁷ that patients with radiographic evidence of calcification of the distal superficial femoral artery and/or popliteal artery were at risk for arterial complications. This finding is also supported by other studies.^8,11 In TKA, damage to arterial structures proximal to the surgical field could manifest as impaired postoperative wound healing or an ischemic limb. Wound healing depends on adequate blood flow to the healing tissue, and any damage to arterial or venous structures can theoretically compromise this process.

Added to vascular/wound complications as concerning complications in orthopedic surgery is venous thromboembolism (VTE). The role of tourniquets in the formation of VTEs is controversial. A tourniquet has the potential to increase the risk for DVT because of the stasis of venous blood in the lower limb or possible damage to calcified blood vessels. Callam and colleagues¹² studied the connection between artery disease and chronic leg ulcers and found that half the patients diagnosed with peripheral artery disease also had stigmata of chronic venous insufficiency. Therefore, the entities can occur in tandem, and surgeons should keep this in mind.

Here we report on a study we conducted to determine whether tourniquet use in TKA in patients with preexisting radiographic evidence of vascular disease increases the risk for wound complications or VTE.

Patients and Methods

We retrospectively reviewed 461 consecutive primary TKAs (373 patients) performed between January 2007 and June 2012 by 2 attending orthopedic surgeons specializing in adult reconstruction. Medical records and operative reports of 583 patients were examined after receiving institutional review board approval. Of these patients, 373 (64%) had a minimum of 12-month follow-up data available. Twelve months was deemed long enough to discover wound complications or DVTs secondary to the index procedure. Most of these outcomes manifest within the first 3 months after surgery and certainly by 12 months. Follow-up longer than 12 months may become a confounder, as wound complications outside the acute to subacute postoperative window could be related to patients’ underlying PVD and not directly to tourniquet use during surgery. Patient demographics and comorbidities were recorded. Comorbidities were obtained from preoperative medical evaluations and surgeons’ preoperative evaluations. All patients had preoperative palpable dorsalis pedis and posterior tibialis arterial pulses. No patient required preoperative vascular studies based on preoperative examination or comorbidities. No patient had prior vascular bypass surgery or stenting.

TKA was performed in a nonlaminar flow, positive-pressure, high-efficiency particulate air-filtered room with sterile toga/surgical helmet systems. For all patients, a pneumatic thigh tourniquet was applied, and the patient was prepared and draped. After limb exsanguination using a rubber bandage, the limb was elevated and the tourniquet inflated to a pressure of 250 to 300 mm Hg. The tourniquet was released either just before closure or immediately after closure in all cases; it was always let down before placement of final bandages.

Prophylactic chemical anticoagulation consisting of warfarin, aspirin, or enoxaparin was used in all patients and continued for 4 to 6 weeks after surgery. All patients received mechanical DVT prophylaxis with sequential compression devices, and all were mobilized out of bed beginning either the day of surgery or the next day. All patients received perioperative intravenous antibiotics, with the preoperative dose given before tourniquet inflation and the last postoperative dose stopped within 24 hours of surgery.

All patients who had primary TKA underwent preoperative medical evaluation and optimization. The patient’s hospital course was monitored closely, and complications noted by the orthopedic team were documented. Follow-up documentation was retrospectively reviewed for evidence of wound complications or VTE. Wound complications were defined as cellulitis, delayed wound healing, wound dehiscence, and/or periprosthetic joint infection. In the case of VTE, physical examination findings were not sufficient for inclusion. Venous duplex ultrasonography demonstrating the clot was reviewed before inclusion.

Preoperative radiographs were examined for arterial calcification (Figure). We refer to calcification seen above the knee joint as proximal calcification and to calcification observed below the joint as distal calcification. Patients exhibited calcification proximally only, distally only, or both proximally and distally. The 373 patients were placed into 2 groups based on whether they had preoperative arterial calcification on plain radiography of the knee. One group (285 patients with no radiographic evidence of preoperative knee arterial calcification) underwent 365 TKAs, and the other group (88 patients with radiographic evidence of preoperative knee arterial calcification) underwent 96 TKAs.

A sample size calculation was performed to determine how many patients were needed in each group with 80% power and an α of 0.05. With an estimated difference in VTE/wound complication rate between the calcification and no-calcification groups of 12%, we needed to review 316 TKAs total. This 12% difference was based on study findings of a 25% complication rate in PVD patients who underwent tourniquet-assisted TKA, and the rate of VTE/wound complication after TKA in patients overall, which can be up to 12%.^7,13,14 We exceeded minimal enrollment and had 461 TKAs. Descriptive statistics were reported, with means and ranges provided where appropriate. Independent t test was used to evaluate the differences in continuous data (age) between the groups. Univariate analysis (using Pearson χ² and Fisher exact tests) and multivariate logistic regression analysis were used to evaluate the effects of categorical variables (sex, comorbidity, calcification [presence, absence], and location of calcification [proximal only, distal only, both]) on wound complication and VTE rates. All tests were 2-tailed and performed with a type I error rate of 0.05. Data analysis was performed with SPSS Version 19.0 (SPSS).

Results

Patient characteristics are summarized in Table 1. Of the 373 patients, 285 lacked calcification, and 88 had calcification. Mean age was 67.73 years (range, 24-92 years) for all patients, 65.99 years (range, 24-89 years) for the no-calcification group, and 74.32 years (range, 54-92 years) for the calcification group; the calcification group demonstrated a trend toward older age, but the difference was not significantly different (P = .07). Of the 373 patients, 156 (41.82%) were male: 110 in the no-calcification group (38.60%) and 46 in the calcification group (52.27%); sex was significantly (P = .002) different between groups, with more males in the calcification group.

Data on total preoperative comorbidities are summarized in Table 2. Hypertension, hyperlipidemia, diabetes, and coronary artery disease (CAD) were the most common comorbidities, and they were all significantly (P ≤ .05) increased in the calcification group.

No patients had reported arterial complications, such as arterial bleeding, aneurysm, intimal tears, or loss of distal pulses. Wound complication after TKA was detected in 3.04% of all cases (Table 3). Rate of DVT after TKA was 2.60% of all cases, and rate of pulmonary embolism after TKA was 2.17% of all cases. Of the 96 TKAs with preoperative radiographic evidence of calcification, 47 (48.96%) had proximal calcification only, 11 (11.46%) had distal calcification only, and 38 (39.58%) had both proximal and distal calcification (Table 4). There was no significant difference between the rate of wound complication or VTE based on location of vascular calcification.

Univariate analysis demonstrated that presence of arterial knee calcification did not increase the risk for postoperative wound complication (odds ratio [OR], 1.04; 95% confidence interval [CI], 0.28-3.80; P > .05) (Table 5). Location of arterial knee calcification also did not increase the risk for postoperative wound complication. In addition, univariate analysis demonstrated that presence of arterial knee calcification did not increase the risk for postoperative VTE (OR, 1.20; 95% CI, 0.43-3.36; P > .05 (Table 6).

Of the 14 wound complications, the most common infections were cellulitis (5/14 cases; 35.71%) and infected hardware that required component revision (5/14 cases; 35.71%). Mean time from TKA to infection was 137.93 days (range, 5-783 days). The most common organism grown in culture from the wound was Staphylococcus (5/14 cases; 35.71%).

Additional univariate statistical analysis revealed that presence of diabetes, hypertension, prior VTE, CAD, and male sex was linked to higher incidence of wound complication (P < .05) (Table 5). When multivariate analysis was performed, hypertension, prior VTE, and male sex remained significant (P < .05) (Table 5).

Discussion

TKA is a safe and effective procedure used to treat osteoarthritis of the knee and improve patients’ quality of life.¹⁵ About 700,000 TKAs are performed annually in the United States.¹⁶ Because of improvements in preventive medicine and medical technology, life expectancy is increasing, and TKAs are now being performed in higher numbers and in an older patient population. Over the next few decades, these developments will lead to more postoperative complications. It is projected that, by 2030, the need for TKAs in the United States will increase by 673% to 3.48 million.¹⁷ Postoperative complications are rare but unfortunately often lead to poor outcomes or even mortality.¹⁸ To help minimize the number of postoperative complications, we must understand the safety of tourniquet use in TKA. Other investigators have concluded that tourniquet use is unsafe in patients with preoperative vascular calcifications on plain radiographs.^7,8,11 The present study, designed to elucidate whether preoperative evidence of knee arterial calcification may predispose TKA patients to postoperative wound complication or VTE, had some important findings.

In our study, wound complication and VTE occurred in a considerable number of patients after TKA. Despite exceeding the number of patients calculated by the power analysis, our population may have been inadequate to fully detect statistical significance. Thus, our conclusion of failing to reject the null hypothesis may have been because of sample size, a type II error. We found that, after primary TKA, 3.04% of patients developed wound complications and 4.77% VTE. According to the literature, the incidence of infection after primary TKA is between 0.5% and 12%, and that of VTE reported within 3 months after TKA is 1.3% to 10%.^13,14 Although we had 100% VTE prophylaxis, meeting the standard of care, VTE after TKA remains a postoperative complication.¹⁹ This study also found that a considerable percentage of primary TKA patients (23.59%) had preoperative calcification of the knee arteries. To our knowledge, this study was the first to quantify the incidence of knee arterial calcification in patients who underwent TKA.

Preoperative calcification of the knee arteries in patients who underwent TKA did not increase the risk for wound complication, VTE, or arterial damage. These calcifications, however, do pose an increased systemic vascular risk.²⁰ Calcification of the vascular wall predicts increased cardiovascular risk, independent of classical cardiovascular risk factors.^3,18,21-24 Clinically, patients who have both diabetes and calcifications are at significant excess risk for total mortality, stroke mortality, and cardiovascular mortality, compared with patients with diabetes but without such calcifications. They also had a significantly higher incidence of coronary heart disease events, stroke events, and lower extremity amputations.^25,26

All our patients underwent tourniquet-assisted TKA. Although previous studies have indicated that tourniquet use may increase arterial complications and wound complications or even limb loss in patients with calcified arteries, we did not find this link.^7,27 Our population had no reported arterial complications related to tourniquet use. Other, smaller studies have had similar findings. Vandenbussche and colleagues²⁸ prospectively studied 80 TKA cases randomized to tourniquet use or no tourniquet use and found no postoperative nerve palsies, wound infections, wound healing problems, or hematomas. Our study is also in accord with studies that have reported tourniquet use did not increase risk for DVT.²⁹ Therefore, unlike earlier data, our data demonstrated that tourniquet use in patients with knee arterial calcification was safe.^7,27,30,31

Patients with calcification were more likely to have the medical comorbidities of hypertension, diabetes, hyperlipidemia, and CAD. All these comorbidities are linked to the development of arterial calcification, or atherosclerotic occlusive disease.^32,33 As life expectancy and the need for TKA increase, it is likely that a larger percentage of TKA patients will have preoperative radiographic evidence of knee arterial calcification. Although current dogma is that tourniquet-assisted TKA is contraindicated for patients with preoperative radiographic evidence of femoral-popliteal calcification, our study results showed that this calcification should not affect preoperative TKA planning for these patients.

We divided our patients into 3 categories: those with proximal calcification (above the joint line), those with distal calcification (below the joint line), and those with both proximal and distal calcification. Location of arterial calcification did not have an effect on their rates of postoperative wound complication or VTE. We hypothesized that patients with proximal calcification would be at increased risk for direct arterial injury and subsequent wound complication because the tourniquet is placed proximally. Previous research has indicated that arterial occlusion and subsequent wound complication can occur because of low blood flow stemming from tourniquet use.⁷ Further, intraoperative manipulation (flexing) of a knee with calcified vessels causes arterial complications after TKA because these vessels are less elastic than nonatheromatous vessels.³¹ However, we found no such effect. At the same time, having arterial calcification might also be an indication of venous disease in this location,¹² which may be especially important for proximal calcifications. Proximal DVT more likely is a precursor to pulmonary embolic events than distal DVT is.^31,34 However, we found no difference in VTE rates among the 3 arterial location groups, which is supported by studies that have found that tourniquet use does not increase DVT incidence.^29,35-40

Risk for wound complications was higher in male patients and in patients with diabetes, prior VTE, hypertension, or CAD. This finding is important because, with the increasing age of patients who undergo TKA, those with serious medical comorbidities will continue to need and have this surgery.¹⁷ Diabetes may increase the rate of wound complication because patients with diabetes have poor microcirculation, poor collagen synthesis, and reduced wound strength.⁴¹ Malinzak and colleagues⁴² demonstrated that, compared with patients without diabetes, those with diabetes had a significantly higher risk for infection after TKA. Prior VTE, specifically DVT, may increase the rate of wound complication because after DVT the deep veins may be damaged and exhibit valvular dysfunction. Labropoulos and colleagues⁴³ showed that DVT history was strongly associated with ulcer nonhealing. Perhaps hypertension has been overlooked as a risk factor for wound complication in TKA. No previous studies have assessed the link between hypertension and wound complications after TKA. However, a study of wound healing after total hip arthroplasty found that, compared with normotensive patients, hypertensive patients had delayed wound healing, putting them at higher risk for infection.⁴⁴ In addition, we found that patients with CAD were at increased risk for wound complications—an unexpected finding, as CAD traditionally is not a risk factor for infection or poor wound healing. Recently, however, CAD was identified as an independent risk factor for surgical site infections in posterior lumbar–instrumented arthrodesis.⁴⁵ The etiology of this association is unknown. Also, male patients were at increased risk for wound complication. Male sex has been implicated as an independent risk factor for development of surgical site infections and has been established as an important predisposing factor for periprosthetic joint infections.⁴⁶

It is possible that patients who present with diabetes, VTE, hypertension, or CAD before TKA should have a consultation with a vascular surgeon or should have TKA performed without a tourniquet, but this conclusion cannot be considered definitive without a large prospective randomized trial or possibly registry data. Our data indicate that patients with these comorbidities have higher rates of wound complications irrespective of preoperative radiographic calcifications. On the basis of our study results, however, we certainly recommend that patients with these risk factors have preoperative medical optimization. Orthopedic surgeons should take a thorough history and perform a meticulous physical examination on these patients to look for evidence of PVD. We recommend that, if vascular claudication is elicited in the history, or if there is evidence of peripheral arterial disease—such as hair loss, skin discoloration, dystrophic nail changes, or absent or unequal peripheral pulses—the ankle-brachial index test should be performed. If the index value is less than 0.9, then a preoperative vascular surgery consultation should be obtained.

This study had some weaknesses. First, it was retrospective, so it is possible that some wound or VTE complications were not reported and thus not found in the paper charts or electronic medical records. Some patients may have had VTE diagnostic scans at other hospitals, and their results may not have been recorded across databases. Moreover, some patients may have seen wound specialists for wound infections or wound healing problems, and these may not have been reported to the orthopedic surgeons. Second, though our patient population was not small, it may not have been of adequate size to fully detect statistical significance. We met our enrollment numbers based on our sample size calculations from an a priori power analysis; however, we still draw conclusions with the possibility of committing a type II error in mind by failing to reject the null hypothesis when in reality a statistically significant difference does exist. Third, none of our consecutive patients carried the preoperative diagnosis of PVD, and none had preoperative vascular surgery. Therefore, though calcifications were noted on radiographs, clinically our patients were asymptomatic with respect to vascular health. Last, the 2 groups were not randomized. All patients underwent tourniquet-assisted TKA.           

Conclusion

To our knowledge, this is the largest study to examine the effect of preoperative knee arterial calcification on wound complication and VTE after tourniquet-assisted TKA. Contrary to previously published recommendations, we conclude that TKA can be safely performed with a tourniquet in the presence of preoperative radiographic evidence of such calcification. However, we recommend that patients with diabetes, hypertension, CAD, or prior VTE undergo an appropriate physical examination to elicit any signs or symptoms of vascular disease. If before surgery there is any question of vascular competence, a vascular surgeon should be consulted.

Tourniquets are often used in total knee arthroplasty (TKA) to improve visualization of structures, shorten operative time, reduce intraoperative bleeding, and improve cementing technique. Despite these advantages, controversy remains regarding the safety of tourniquet use. Tourniquets have been associated with nerve palsies, vascular injury, and muscle damage.^1-5 Some have hypothesized they may cause venous stasis or direct endothelial damage that may develop into deep vein thrombosis (DVT). Abdel-Salam and Eyres⁶ found an increased incidence of postoperative wound complications and DVTs associated with tourniquet use.

Moreover, investigators have analyzed the role of tourniquets in populations at high risk for wound complications. DeLaurentis and colleagues⁷ performed a prospective and retrospective analysis of 1182 TKA patients, 24 (2%) of whom had preexisting peripheral vascular disease (PVD), defined as a history of arterial insufficiency, absent dorsalis pedis and/or absent posterior tibial pulsations, and arterial calcifications. A tourniquet was used in each case. Arterial complications occurred in 6 of the 24 patients with PVD. As expected, the authors found that a history of intermittent claudication, pain at rest, and arterial ulcers resulted in a high risk for vascular complications. Further studies have supported this finding and expanded the list of predisposing factors to include previous vascular surgery and absent and asymmetric pedal pulsations.^7-11 Of particular concern to total joint arthroplasty surgeons was the finding by DeLaurentis and colleagues⁷ that patients with radiographic evidence of calcification of the distal superficial femoral artery and/or popliteal artery were at risk for arterial complications. This finding is also supported by other studies.^8,11 In TKA, damage to arterial structures proximal to the surgical field could manifest as impaired postoperative wound healing or an ischemic limb. Wound healing depends on adequate blood flow to the healing tissue, and any damage to arterial or venous structures can theoretically compromise this process.

Added to vascular/wound complications as concerning complications in orthopedic surgery is venous thromboembolism (VTE). The role of tourniquets in the formation of VTEs is controversial. A tourniquet has the potential to increase the risk for DVT because of the stasis of venous blood in the lower limb or possible damage to calcified blood vessels. Callam and colleagues¹² studied the connection between artery disease and chronic leg ulcers and found that half the patients diagnosed with peripheral artery disease also had stigmata of chronic venous insufficiency. Therefore, the entities can occur in tandem, and surgeons should keep this in mind.

Here we report on a study we conducted to determine whether tourniquet use in TKA in patients with preexisting radiographic evidence of vascular disease increases the risk for wound complications or VTE.

Patients and Methods

We retrospectively reviewed 461 consecutive primary TKAs (373 patients) performed between January 2007 and June 2012 by 2 attending orthopedic surgeons specializing in adult reconstruction. Medical records and operative reports of 583 patients were examined after receiving institutional review board approval. Of these patients, 373 (64%) had a minimum of 12-month follow-up data available. Twelve months was deemed long enough to discover wound complications or DVTs secondary to the index procedure. Most of these outcomes manifest within the first 3 months after surgery and certainly by 12 months. Follow-up longer than 12 months may become a confounder, as wound complications outside the acute to subacute postoperative window could be related to patients’ underlying PVD and not directly to tourniquet use during surgery. Patient demographics and comorbidities were recorded. Comorbidities were obtained from preoperative medical evaluations and surgeons’ preoperative evaluations. All patients had preoperative palpable dorsalis pedis and posterior tibialis arterial pulses. No patient required preoperative vascular studies based on preoperative examination or comorbidities. No patient had prior vascular bypass surgery or stenting.

TKA was performed in a nonlaminar flow, positive-pressure, high-efficiency particulate air-filtered room with sterile toga/surgical helmet systems. For all patients, a pneumatic thigh tourniquet was applied, and the patient was prepared and draped. After limb exsanguination using a rubber bandage, the limb was elevated and the tourniquet inflated to a pressure of 250 to 300 mm Hg. The tourniquet was released either just before closure or immediately after closure in all cases; it was always let down before placement of final bandages.

Prophylactic chemical anticoagulation consisting of warfarin, aspirin, or enoxaparin was used in all patients and continued for 4 to 6 weeks after surgery. All patients received mechanical DVT prophylaxis with sequential compression devices, and all were mobilized out of bed beginning either the day of surgery or the next day. All patients received perioperative intravenous antibiotics, with the preoperative dose given before tourniquet inflation and the last postoperative dose stopped within 24 hours of surgery.

All patients who had primary TKA underwent preoperative medical evaluation and optimization. The patient’s hospital course was monitored closely, and complications noted by the orthopedic team were documented. Follow-up documentation was retrospectively reviewed for evidence of wound complications or VTE. Wound complications were defined as cellulitis, delayed wound healing, wound dehiscence, and/or periprosthetic joint infection. In the case of VTE, physical examination findings were not sufficient for inclusion. Venous duplex ultrasonography demonstrating the clot was reviewed before inclusion.

Preoperative radiographs were examined for arterial calcification (Figure). We refer to calcification seen above the knee joint as proximal calcification and to calcification observed below the joint as distal calcification. Patients exhibited calcification proximally only, distally only, or both proximally and distally. The 373 patients were placed into 2 groups based on whether they had preoperative arterial calcification on plain radiography of the knee. One group (285 patients with no radiographic evidence of preoperative knee arterial calcification) underwent 365 TKAs, and the other group (88 patients with radiographic evidence of preoperative knee arterial calcification) underwent 96 TKAs.

A sample size calculation was performed to determine how many patients were needed in each group with 80% power and an α of 0.05. With an estimated difference in VTE/wound complication rate between the calcification and no-calcification groups of 12%, we needed to review 316 TKAs total. This 12% difference was based on study findings of a 25% complication rate in PVD patients who underwent tourniquet-assisted TKA, and the rate of VTE/wound complication after TKA in patients overall, which can be up to 12%.^7,13,14 We exceeded minimal enrollment and had 461 TKAs. Descriptive statistics were reported, with means and ranges provided where appropriate. Independent t test was used to evaluate the differences in continuous data (age) between the groups. Univariate analysis (using Pearson χ² and Fisher exact tests) and multivariate logistic regression analysis were used to evaluate the effects of categorical variables (sex, comorbidity, calcification [presence, absence], and location of calcification [proximal only, distal only, both]) on wound complication and VTE rates. All tests were 2-tailed and performed with a type I error rate of 0.05. Data analysis was performed with SPSS Version 19.0 (SPSS).

Results

Patient characteristics are summarized in Table 1. Of the 373 patients, 285 lacked calcification, and 88 had calcification. Mean age was 67.73 years (range, 24-92 years) for all patients, 65.99 years (range, 24-89 years) for the no-calcification group, and 74.32 years (range, 54-92 years) for the calcification group; the calcification group demonstrated a trend toward older age, but the difference was not significantly different (P = .07). Of the 373 patients, 156 (41.82%) were male: 110 in the no-calcification group (38.60%) and 46 in the calcification group (52.27%); sex was significantly (P = .002) different between groups, with more males in the calcification group.

Data on total preoperative comorbidities are summarized in Table 2. Hypertension, hyperlipidemia, diabetes, and coronary artery disease (CAD) were the most common comorbidities, and they were all significantly (P ≤ .05) increased in the calcification group.

No patients had reported arterial complications, such as arterial bleeding, aneurysm, intimal tears, or loss of distal pulses. Wound complication after TKA was detected in 3.04% of all cases (Table 3). Rate of DVT after TKA was 2.60% of all cases, and rate of pulmonary embolism after TKA was 2.17% of all cases. Of the 96 TKAs with preoperative radiographic evidence of calcification, 47 (48.96%) had proximal calcification only, 11 (11.46%) had distal calcification only, and 38 (39.58%) had both proximal and distal calcification (Table 4). There was no significant difference between the rate of wound complication or VTE based on location of vascular calcification.

Univariate analysis demonstrated that presence of arterial knee calcification did not increase the risk for postoperative wound complication (odds ratio [OR], 1.04; 95% confidence interval [CI], 0.28-3.80; P > .05) (Table 5). Location of arterial knee calcification also did not increase the risk for postoperative wound complication. In addition, univariate analysis demonstrated that presence of arterial knee calcification did not increase the risk for postoperative VTE (OR, 1.20; 95% CI, 0.43-3.36; P > .05 (Table 6).

Of the 14 wound complications, the most common infections were cellulitis (5/14 cases; 35.71%) and infected hardware that required component revision (5/14 cases; 35.71%). Mean time from TKA to infection was 137.93 days (range, 5-783 days). The most common organism grown in culture from the wound was Staphylococcus (5/14 cases; 35.71%).

Additional univariate statistical analysis revealed that presence of diabetes, hypertension, prior VTE, CAD, and male sex was linked to higher incidence of wound complication (P < .05) (Table 5). When multivariate analysis was performed, hypertension, prior VTE, and male sex remained significant (P < .05) (Table 5).

Discussion

TKA is a safe and effective procedure used to treat osteoarthritis of the knee and improve patients’ quality of life.¹⁵ About 700,000 TKAs are performed annually in the United States.¹⁶ Because of improvements in preventive medicine and medical technology, life expectancy is increasing, and TKAs are now being performed in higher numbers and in an older patient population. Over the next few decades, these developments will lead to more postoperative complications. It is projected that, by 2030, the need for TKAs in the United States will increase by 673% to 3.48 million.¹⁷ Postoperative complications are rare but unfortunately often lead to poor outcomes or even mortality.¹⁸ To help minimize the number of postoperative complications, we must understand the safety of tourniquet use in TKA. Other investigators have concluded that tourniquet use is unsafe in patients with preoperative vascular calcifications on plain radiographs.^7,8,11 The present study, designed to elucidate whether preoperative evidence of knee arterial calcification may predispose TKA patients to postoperative wound complication or VTE, had some important findings.

In our study, wound complication and VTE occurred in a considerable number of patients after TKA. Despite exceeding the number of patients calculated by the power analysis, our population may have been inadequate to fully detect statistical significance. Thus, our conclusion of failing to reject the null hypothesis may have been because of sample size, a type II error. We found that, after primary TKA, 3.04% of patients developed wound complications and 4.77% VTE. According to the literature, the incidence of infection after primary TKA is between 0.5% and 12%, and that of VTE reported within 3 months after TKA is 1.3% to 10%.^13,14 Although we had 100% VTE prophylaxis, meeting the standard of care, VTE after TKA remains a postoperative complication.¹⁹ This study also found that a considerable percentage of primary TKA patients (23.59%) had preoperative calcification of the knee arteries. To our knowledge, this study was the first to quantify the incidence of knee arterial calcification in patients who underwent TKA.

Preoperative calcification of the knee arteries in patients who underwent TKA did not increase the risk for wound complication, VTE, or arterial damage. These calcifications, however, do pose an increased systemic vascular risk.²⁰ Calcification of the vascular wall predicts increased cardiovascular risk, independent of classical cardiovascular risk factors.^3,18,21-24 Clinically, patients who have both diabetes and calcifications are at significant excess risk for total mortality, stroke mortality, and cardiovascular mortality, compared with patients with diabetes but without such calcifications. They also had a significantly higher incidence of coronary heart disease events, stroke events, and lower extremity amputations.^25,26

All our patients underwent tourniquet-assisted TKA. Although previous studies have indicated that tourniquet use may increase arterial complications and wound complications or even limb loss in patients with calcified arteries, we did not find this link.^7,27 Our population had no reported arterial complications related to tourniquet use. Other, smaller studies have had similar findings. Vandenbussche and colleagues²⁸ prospectively studied 80 TKA cases randomized to tourniquet use or no tourniquet use and found no postoperative nerve palsies, wound infections, wound healing problems, or hematomas. Our study is also in accord with studies that have reported tourniquet use did not increase risk for DVT.²⁹ Therefore, unlike earlier data, our data demonstrated that tourniquet use in patients with knee arterial calcification was safe.^7,27,30,31

Patients with calcification were more likely to have the medical comorbidities of hypertension, diabetes, hyperlipidemia, and CAD. All these comorbidities are linked to the development of arterial calcification, or atherosclerotic occlusive disease.^32,33 As life expectancy and the need for TKA increase, it is likely that a larger percentage of TKA patients will have preoperative radiographic evidence of knee arterial calcification. Although current dogma is that tourniquet-assisted TKA is contraindicated for patients with preoperative radiographic evidence of femoral-popliteal calcification, our study results showed that this calcification should not affect preoperative TKA planning for these patients.

We divided our patients into 3 categories: those with proximal calcification (above the joint line), those with distal calcification (below the joint line), and those with both proximal and distal calcification. Location of arterial calcification did not have an effect on their rates of postoperative wound complication or VTE. We hypothesized that patients with proximal calcification would be at increased risk for direct arterial injury and subsequent wound complication because the tourniquet is placed proximally. Previous research has indicated that arterial occlusion and subsequent wound complication can occur because of low blood flow stemming from tourniquet use.⁷ Further, intraoperative manipulation (flexing) of a knee with calcified vessels causes arterial complications after TKA because these vessels are less elastic than nonatheromatous vessels.³¹ However, we found no such effect. At the same time, having arterial calcification might also be an indication of venous disease in this location,¹² which may be especially important for proximal calcifications. Proximal DVT more likely is a precursor to pulmonary embolic events than distal DVT is.^31,34 However, we found no difference in VTE rates among the 3 arterial location groups, which is supported by studies that have found that tourniquet use does not increase DVT incidence.^29,35-40

Risk for wound complications was higher in male patients and in patients with diabetes, prior VTE, hypertension, or CAD. This finding is important because, with the increasing age of patients who undergo TKA, those with serious medical comorbidities will continue to need and have this surgery.¹⁷ Diabetes may increase the rate of wound complication because patients with diabetes have poor microcirculation, poor collagen synthesis, and reduced wound strength.⁴¹ Malinzak and colleagues⁴² demonstrated that, compared with patients without diabetes, those with diabetes had a significantly higher risk for infection after TKA. Prior VTE, specifically DVT, may increase the rate of wound complication because after DVT the deep veins may be damaged and exhibit valvular dysfunction. Labropoulos and colleagues⁴³ showed that DVT history was strongly associated with ulcer nonhealing. Perhaps hypertension has been overlooked as a risk factor for wound complication in TKA. No previous studies have assessed the link between hypertension and wound complications after TKA. However, a study of wound healing after total hip arthroplasty found that, compared with normotensive patients, hypertensive patients had delayed wound healing, putting them at higher risk for infection.⁴⁴ In addition, we found that patients with CAD were at increased risk for wound complications—an unexpected finding, as CAD traditionally is not a risk factor for infection or poor wound healing. Recently, however, CAD was identified as an independent risk factor for surgical site infections in posterior lumbar–instrumented arthrodesis.⁴⁵ The etiology of this association is unknown. Also, male patients were at increased risk for wound complication. Male sex has been implicated as an independent risk factor for development of surgical site infections and has been established as an important predisposing factor for periprosthetic joint infections.⁴⁶

It is possible that patients who present with diabetes, VTE, hypertension, or CAD before TKA should have a consultation with a vascular surgeon or should have TKA performed without a tourniquet, but this conclusion cannot be considered definitive without a large prospective randomized trial or possibly registry data. Our data indicate that patients with these comorbidities have higher rates of wound complications irrespective of preoperative radiographic calcifications. On the basis of our study results, however, we certainly recommend that patients with these risk factors have preoperative medical optimization. Orthopedic surgeons should take a thorough history and perform a meticulous physical examination on these patients to look for evidence of PVD. We recommend that, if vascular claudication is elicited in the history, or if there is evidence of peripheral arterial disease—such as hair loss, skin discoloration, dystrophic nail changes, or absent or unequal peripheral pulses—the ankle-brachial index test should be performed. If the index value is less than 0.9, then a preoperative vascular surgery consultation should be obtained.

This study had some weaknesses. First, it was retrospective, so it is possible that some wound or VTE complications were not reported and thus not found in the paper charts or electronic medical records. Some patients may have had VTE diagnostic scans at other hospitals, and their results may not have been recorded across databases. Moreover, some patients may have seen wound specialists for wound infections or wound healing problems, and these may not have been reported to the orthopedic surgeons. Second, though our patient population was not small, it may not have been of adequate size to fully detect statistical significance. We met our enrollment numbers based on our sample size calculations from an a priori power analysis; however, we still draw conclusions with the possibility of committing a type II error in mind by failing to reject the null hypothesis when in reality a statistically significant difference does exist. Third, none of our consecutive patients carried the preoperative diagnosis of PVD, and none had preoperative vascular surgery. Therefore, though calcifications were noted on radiographs, clinically our patients were asymptomatic with respect to vascular health. Last, the 2 groups were not randomized. All patients underwent tourniquet-assisted TKA.           

Conclusion

To our knowledge, this is the largest study to examine the effect of preoperative knee arterial calcification on wound complication and VTE after tourniquet-assisted TKA. Contrary to previously published recommendations, we conclude that TKA can be safely performed with a tourniquet in the presence of preoperative radiographic evidence of such calcification. However, we recommend that patients with diabetes, hypertension, CAD, or prior VTE undergo an appropriate physical examination to elicit any signs or symptoms of vascular disease. If before surgery there is any question of vascular competence, a vascular surgeon should be consulted.

Tourniquets are often used in total knee arthroplasty (TKA) to improve visualization of structures, shorten operative time, reduce intraoperative bleeding, and improve cementing technique. Despite these advantages, controversy remains regarding the safety of tourniquet use. Tourniquets have been associated with nerve palsies, vascular injury, and muscle damage.^1-5 Some have hypothesized they may cause venous stasis or direct endothelial damage that may develop into deep vein thrombosis (DVT). Abdel-Salam and Eyres⁶ found an increased incidence of postoperative wound complications and DVTs associated with tourniquet use.

Moreover, investigators have analyzed the role of tourniquets in populations at high risk for wound complications. DeLaurentis and colleagues⁷ performed a prospective and retrospective analysis of 1182 TKA patients, 24 (2%) of whom had preexisting peripheral vascular disease (PVD), defined as a history of arterial insufficiency, absent dorsalis pedis and/or absent posterior tibial pulsations, and arterial calcifications. A tourniquet was used in each case. Arterial complications occurred in 6 of the 24 patients with PVD. As expected, the authors found that a history of intermittent claudication, pain at rest, and arterial ulcers resulted in a high risk for vascular complications. Further studies have supported this finding and expanded the list of predisposing factors to include previous vascular surgery and absent and asymmetric pedal pulsations.^7-11 Of particular concern to total joint arthroplasty surgeons was the finding by DeLaurentis and colleagues⁷ that patients with radiographic evidence of calcification of the distal superficial femoral artery and/or popliteal artery were at risk for arterial complications. This finding is also supported by other studies.^8,11 In TKA, damage to arterial structures proximal to the surgical field could manifest as impaired postoperative wound healing or an ischemic limb. Wound healing depends on adequate blood flow to the healing tissue, and any damage to arterial or venous structures can theoretically compromise this process.

Added to vascular/wound complications as concerning complications in orthopedic surgery is venous thromboembolism (VTE). The role of tourniquets in the formation of VTEs is controversial. A tourniquet has the potential to increase the risk for DVT because of the stasis of venous blood in the lower limb or possible damage to calcified blood vessels. Callam and colleagues¹² studied the connection between artery disease and chronic leg ulcers and found that half the patients diagnosed with peripheral artery disease also had stigmata of chronic venous insufficiency. Therefore, the entities can occur in tandem, and surgeons should keep this in mind.

Here we report on a study we conducted to determine whether tourniquet use in TKA in patients with preexisting radiographic evidence of vascular disease increases the risk for wound complications or VTE.

Patients and Methods

We retrospectively reviewed 461 consecutive primary TKAs (373 patients) performed between January 2007 and June 2012 by 2 attending orthopedic surgeons specializing in adult reconstruction. Medical records and operative reports of 583 patients were examined after receiving institutional review board approval. Of these patients, 373 (64%) had a minimum of 12-month follow-up data available. Twelve months was deemed long enough to discover wound complications or DVTs secondary to the index procedure. Most of these outcomes manifest within the first 3 months after surgery and certainly by 12 months. Follow-up longer than 12 months may become a confounder, as wound complications outside the acute to subacute postoperative window could be related to patients’ underlying PVD and not directly to tourniquet use during surgery. Patient demographics and comorbidities were recorded. Comorbidities were obtained from preoperative medical evaluations and surgeons’ preoperative evaluations. All patients had preoperative palpable dorsalis pedis and posterior tibialis arterial pulses. No patient required preoperative vascular studies based on preoperative examination or comorbidities. No patient had prior vascular bypass surgery or stenting.

TKA was performed in a nonlaminar flow, positive-pressure, high-efficiency particulate air-filtered room with sterile toga/surgical helmet systems. For all patients, a pneumatic thigh tourniquet was applied, and the patient was prepared and draped. After limb exsanguination using a rubber bandage, the limb was elevated and the tourniquet inflated to a pressure of 250 to 300 mm Hg. The tourniquet was released either just before closure or immediately after closure in all cases; it was always let down before placement of final bandages.

Prophylactic chemical anticoagulation consisting of warfarin, aspirin, or enoxaparin was used in all patients and continued for 4 to 6 weeks after surgery. All patients received mechanical DVT prophylaxis with sequential compression devices, and all were mobilized out of bed beginning either the day of surgery or the next day. All patients received perioperative intravenous antibiotics, with the preoperative dose given before tourniquet inflation and the last postoperative dose stopped within 24 hours of surgery.

All patients who had primary TKA underwent preoperative medical evaluation and optimization. The patient’s hospital course was monitored closely, and complications noted by the orthopedic team were documented. Follow-up documentation was retrospectively reviewed for evidence of wound complications or VTE. Wound complications were defined as cellulitis, delayed wound healing, wound dehiscence, and/or periprosthetic joint infection. In the case of VTE, physical examination findings were not sufficient for inclusion. Venous duplex ultrasonography demonstrating the clot was reviewed before inclusion.

Preoperative radiographs were examined for arterial calcification (Figure). We refer to calcification seen above the knee joint as proximal calcification and to calcification observed below the joint as distal calcification. Patients exhibited calcification proximally only, distally only, or both proximally and distally. The 373 patients were placed into 2 groups based on whether they had preoperative arterial calcification on plain radiography of the knee. One group (285 patients with no radiographic evidence of preoperative knee arterial calcification) underwent 365 TKAs, and the other group (88 patients with radiographic evidence of preoperative knee arterial calcification) underwent 96 TKAs.

A sample size calculation was performed to determine how many patients were needed in each group with 80% power and an α of 0.05. With an estimated difference in VTE/wound complication rate between the calcification and no-calcification groups of 12%, we needed to review 316 TKAs total. This 12% difference was based on study findings of a 25% complication rate in PVD patients who underwent tourniquet-assisted TKA, and the rate of VTE/wound complication after TKA in patients overall, which can be up to 12%.^7,13,14 We exceeded minimal enrollment and had 461 TKAs. Descriptive statistics were reported, with means and ranges provided where appropriate. Independent t test was used to evaluate the differences in continuous data (age) between the groups. Univariate analysis (using Pearson χ² and Fisher exact tests) and multivariate logistic regression analysis were used to evaluate the effects of categorical variables (sex, comorbidity, calcification [presence, absence], and location of calcification [proximal only, distal only, both]) on wound complication and VTE rates. All tests were 2-tailed and performed with a type I error rate of 0.05. Data analysis was performed with SPSS Version 19.0 (SPSS).

Results

Patient characteristics are summarized in Table 1. Of the 373 patients, 285 lacked calcification, and 88 had calcification. Mean age was 67.73 years (range, 24-92 years) for all patients, 65.99 years (range, 24-89 years) for the no-calcification group, and 74.32 years (range, 54-92 years) for the calcification group; the calcification group demonstrated a trend toward older age, but the difference was not significantly different (P = .07). Of the 373 patients, 156 (41.82%) were male: 110 in the no-calcification group (38.60%) and 46 in the calcification group (52.27%); sex was significantly (P = .002) different between groups, with more males in the calcification group.

Data on total preoperative comorbidities are summarized in Table 2. Hypertension, hyperlipidemia, diabetes, and coronary artery disease (CAD) were the most common comorbidities, and they were all significantly (P ≤ .05) increased in the calcification group.

No patients had reported arterial complications, such as arterial bleeding, aneurysm, intimal tears, or loss of distal pulses. Wound complication after TKA was detected in 3.04% of all cases (Table 3). Rate of DVT after TKA was 2.60% of all cases, and rate of pulmonary embolism after TKA was 2.17% of all cases. Of the 96 TKAs with preoperative radiographic evidence of calcification, 47 (48.96%) had proximal calcification only, 11 (11.46%) had distal calcification only, and 38 (39.58%) had both proximal and distal calcification (Table 4). There was no significant difference between the rate of wound complication or VTE based on location of vascular calcification.

Univariate analysis demonstrated that presence of arterial knee calcification did not increase the risk for postoperative wound complication (odds ratio [OR], 1.04; 95% confidence interval [CI], 0.28-3.80; P > .05) (Table 5). Location of arterial knee calcification also did not increase the risk for postoperative wound complication. In addition, univariate analysis demonstrated that presence of arterial knee calcification did not increase the risk for postoperative VTE (OR, 1.20; 95% CI, 0.43-3.36; P > .05 (Table 6).

Of the 14 wound complications, the most common infections were cellulitis (5/14 cases; 35.71%) and infected hardware that required component revision (5/14 cases; 35.71%). Mean time from TKA to infection was 137.93 days (range, 5-783 days). The most common organism grown in culture from the wound was Staphylococcus (5/14 cases; 35.71%).

Additional univariate statistical analysis revealed that presence of diabetes, hypertension, prior VTE, CAD, and male sex was linked to higher incidence of wound complication (P < .05) (Table 5). When multivariate analysis was performed, hypertension, prior VTE, and male sex remained significant (P < .05) (Table 5).

Discussion

TKA is a safe and effective procedure used to treat osteoarthritis of the knee and improve patients’ quality of life.¹⁵ About 700,000 TKAs are performed annually in the United States.¹⁶ Because of improvements in preventive medicine and medical technology, life expectancy is increasing, and TKAs are now being performed in higher numbers and in an older patient population. Over the next few decades, these developments will lead to more postoperative complications. It is projected that, by 2030, the need for TKAs in the United States will increase by 673% to 3.48 million.¹⁷ Postoperative complications are rare but unfortunately often lead to poor outcomes or even mortality.¹⁸ To help minimize the number of postoperative complications, we must understand the safety of tourniquet use in TKA. Other investigators have concluded that tourniquet use is unsafe in patients with preoperative vascular calcifications on plain radiographs.^7,8,11 The present study, designed to elucidate whether preoperative evidence of knee arterial calcification may predispose TKA patients to postoperative wound complication or VTE, had some important findings.

In our study, wound complication and VTE occurred in a considerable number of patients after TKA. Despite exceeding the number of patients calculated by the power analysis, our population may have been inadequate to fully detect statistical significance. Thus, our conclusion of failing to reject the null hypothesis may have been because of sample size, a type II error. We found that, after primary TKA, 3.04% of patients developed wound complications and 4.77% VTE. According to the literature, the incidence of infection after primary TKA is between 0.5% and 12%, and that of VTE reported within 3 months after TKA is 1.3% to 10%.^13,14 Although we had 100% VTE prophylaxis, meeting the standard of care, VTE after TKA remains a postoperative complication.¹⁹ This study also found that a considerable percentage of primary TKA patients (23.59%) had preoperative calcification of the knee arteries. To our knowledge, this study was the first to quantify the incidence of knee arterial calcification in patients who underwent TKA.

Preoperative calcification of the knee arteries in patients who underwent TKA did not increase the risk for wound complication, VTE, or arterial damage. These calcifications, however, do pose an increased systemic vascular risk.²⁰ Calcification of the vascular wall predicts increased cardiovascular risk, independent of classical cardiovascular risk factors.^3,18,21-24 Clinically, patients who have both diabetes and calcifications are at significant excess risk for total mortality, stroke mortality, and cardiovascular mortality, compared with patients with diabetes but without such calcifications. They also had a significantly higher incidence of coronary heart disease events, stroke events, and lower extremity amputations.^25,26

All our patients underwent tourniquet-assisted TKA. Although previous studies have indicated that tourniquet use may increase arterial complications and wound complications or even limb loss in patients with calcified arteries, we did not find this link.^7,27 Our population had no reported arterial complications related to tourniquet use. Other, smaller studies have had similar findings. Vandenbussche and colleagues²⁸ prospectively studied 80 TKA cases randomized to tourniquet use or no tourniquet use and found no postoperative nerve palsies, wound infections, wound healing problems, or hematomas. Our study is also in accord with studies that have reported tourniquet use did not increase risk for DVT.²⁹ Therefore, unlike earlier data, our data demonstrated that tourniquet use in patients with knee arterial calcification was safe.^7,27,30,31

Patients with calcification were more likely to have the medical comorbidities of hypertension, diabetes, hyperlipidemia, and CAD. All these comorbidities are linked to the development of arterial calcification, or atherosclerotic occlusive disease.^32,33 As life expectancy and the need for TKA increase, it is likely that a larger percentage of TKA patients will have preoperative radiographic evidence of knee arterial calcification. Although current dogma is that tourniquet-assisted TKA is contraindicated for patients with preoperative radiographic evidence of femoral-popliteal calcification, our study results showed that this calcification should not affect preoperative TKA planning for these patients.

We divided our patients into 3 categories: those with proximal calcification (above the joint line), those with distal calcification (below the joint line), and those with both proximal and distal calcification. Location of arterial calcification did not have an effect on their rates of postoperative wound complication or VTE. We hypothesized that patients with proximal calcification would be at increased risk for direct arterial injury and subsequent wound complication because the tourniquet is placed proximally. Previous research has indicated that arterial occlusion and subsequent wound complication can occur because of low blood flow stemming from tourniquet use.⁷ Further, intraoperative manipulation (flexing) of a knee with calcified vessels causes arterial complications after TKA because these vessels are less elastic than nonatheromatous vessels.³¹ However, we found no such effect. At the same time, having arterial calcification might also be an indication of venous disease in this location,¹² which may be especially important for proximal calcifications. Proximal DVT more likely is a precursor to pulmonary embolic events than distal DVT is.^31,34 However, we found no difference in VTE rates among the 3 arterial location groups, which is supported by studies that have found that tourniquet use does not increase DVT incidence.^29,35-40

Risk for wound complications was higher in male patients and in patients with diabetes, prior VTE, hypertension, or CAD. This finding is important because, with the increasing age of patients who undergo TKA, those with serious medical comorbidities will continue to need and have this surgery.¹⁷ Diabetes may increase the rate of wound complication because patients with diabetes have poor microcirculation, poor collagen synthesis, and reduced wound strength.⁴¹ Malinzak and colleagues⁴² demonstrated that, compared with patients without diabetes, those with diabetes had a significantly higher risk for infection after TKA. Prior VTE, specifically DVT, may increase the rate of wound complication because after DVT the deep veins may be damaged and exhibit valvular dysfunction. Labropoulos and colleagues⁴³ showed that DVT history was strongly associated with ulcer nonhealing. Perhaps hypertension has been overlooked as a risk factor for wound complication in TKA. No previous studies have assessed the link between hypertension and wound complications after TKA. However, a study of wound healing after total hip arthroplasty found that, compared with normotensive patients, hypertensive patients had delayed wound healing, putting them at higher risk for infection.⁴⁴ In addition, we found that patients with CAD were at increased risk for wound complications—an unexpected finding, as CAD traditionally is not a risk factor for infection or poor wound healing. Recently, however, CAD was identified as an independent risk factor for surgical site infections in posterior lumbar–instrumented arthrodesis.⁴⁵ The etiology of this association is unknown. Also, male patients were at increased risk for wound complication. Male sex has been implicated as an independent risk factor for development of surgical site infections and has been established as an important predisposing factor for periprosthetic joint infections.⁴⁶

It is possible that patients who present with diabetes, VTE, hypertension, or CAD before TKA should have a consultation with a vascular surgeon or should have TKA performed without a tourniquet, but this conclusion cannot be considered definitive without a large prospective randomized trial or possibly registry data. Our data indicate that patients with these comorbidities have higher rates of wound complications irrespective of preoperative radiographic calcifications. On the basis of our study results, however, we certainly recommend that patients with these risk factors have preoperative medical optimization. Orthopedic surgeons should take a thorough history and perform a meticulous physical examination on these patients to look for evidence of PVD. We recommend that, if vascular claudication is elicited in the history, or if there is evidence of peripheral arterial disease—such as hair loss, skin discoloration, dystrophic nail changes, or absent or unequal peripheral pulses—the ankle-brachial index test should be performed. If the index value is less than 0.9, then a preoperative vascular surgery consultation should be obtained.

This study had some weaknesses. First, it was retrospective, so it is possible that some wound or VTE complications were not reported and thus not found in the paper charts or electronic medical records. Some patients may have had VTE diagnostic scans at other hospitals, and their results may not have been recorded across databases. Moreover, some patients may have seen wound specialists for wound infections or wound healing problems, and these may not have been reported to the orthopedic surgeons. Second, though our patient population was not small, it may not have been of adequate size to fully detect statistical significance. We met our enrollment numbers based on our sample size calculations from an a priori power analysis; however, we still draw conclusions with the possibility of committing a type II error in mind by failing to reject the null hypothesis when in reality a statistically significant difference does exist. Third, none of our consecutive patients carried the preoperative diagnosis of PVD, and none had preoperative vascular surgery. Therefore, though calcifications were noted on radiographs, clinically our patients were asymptomatic with respect to vascular health. Last, the 2 groups were not randomized. All patients underwent tourniquet-assisted TKA.           

Conclusion

To our knowledge, this is the largest study to examine the effect of preoperative knee arterial calcification on wound complication and VTE after tourniquet-assisted TKA. Contrary to previously published recommendations, we conclude that TKA can be safely performed with a tourniquet in the presence of preoperative radiographic evidence of such calcification. However, we recommend that patients with diabetes, hypertension, CAD, or prior VTE undergo an appropriate physical examination to elicit any signs or symptoms of vascular disease. If before surgery there is any question of vascular competence, a vascular surgeon should be consulted.

Perilunate injuries typically stem from a high-energy insult to the carpus. Because of their relative infrequency and often subtle radiographic and physical examination findings, these injuries are often undetected in the emergency department setting.¹ Early anatomic reduction of any carpal malalignment is essential. Even with optimal treatment, complications such as generalized wrist stiffness, diminished grip strength, and posttraumatic arthritis, commonly develop; however, recent studies suggest these issues are often well tolerated.^1-5 In this article, the diagnosis, treatment, and outcomes after perilunate injuries are examined. 

History and Physical Examination

Perilunate injuries result from high-energy trauma to the carpus. Patients with these injuries often present with vague wrist pain and loss of wrist motion. Their fingers are frequently held in slight flexion. The patient may complain of numbness and tingling in the median nerve distribution. An acute carpal tunnel syndrome can rapidly develop. The general belief is that acute carpal tunnel syndrome occurs more commonly in pure volar lunate dislocations than in dorsal perilunate dislocations. However, no studies compare the incidence of acute carpal tunnel syndrome in lunate versus perilunate dislocations.

Radiographic Evaluation

Standard radiographic evaluation of a potential perilunate injury includes posteroanterior (PA), lateral, and oblique views of the wrist (Figure 1). A scaphoid view (ie, PA view with the wrist in ulnar deviation) may also be helpful. The PA view is particularly helpful because it enables assessment of Gilula lines, which are imaginary lines drawn across the proximal and distal aspects of the proximal carpal row and the proximal aspect of the distal carpal row. These lines should appear as 3 smooth arcs running nearly parallel to each other.⁶ Any disruption in these lines suggests carpal incongruity. It may be possible to note a triangular-shaped lunate on the PA view, which is a sign of lunate dislocation.⁷ 

While the PA view is certainly useful, the lateral view is the most important in diagnosing a perilunate injury. The lateral view allows assessment of the collinearity of radius, lunate, and capitate. Any disruption in this collinearity strongly suggests a perilunate dislocation.^7,8 

Classification

Mayfield and colleagues^9,10 described 4 stages of perilunate instability proceeding from a radial to an ulnar direction around the lunate. Stage I involves disruption of the scapholunate joint, while stage II involves both the scapholunate and capitolunate joints. In stage III, the scapholunate, capitolunate, and lunotriquetral ligaments are disrupted, and the result is a perilunate dislocation, usually dorsal. Finally, in stage IV, all the ligaments surrounding the lunate are disrupted and the lunate dislocates, most often volarly.

Lastly, perilunate injuries can be classified as greater-arc injuries if concomitant fracture of the carpus occurs, lesser-arc injuries if the injury is purely ligamentous, or inferior-arc injuries if there is an associated fracture of the volar rim of the distal radius.⁸

Treatment

Closed Reduction

All acute perilunate dislocations should be managed initially with an attempted closed reduction.¹¹ If the injury is older than 72 hours, such an attempt may be futile. For any closed reduction performed in the emergency department setting, intravenous sedation is generally advised for muscle relaxation. Gentle traction with finger traps can also be used prior to the reduction attempt. For a dorsal perilunate dislocation, longitudinal traction followed by volar flexion of the wrist with volar pressure on the lunate and dorsal pressure on the capitate (ie, Tavernier’s maneuver) is required. Once reduction is complete, PA and lateral views of the wrist should be obtained to assess carpal alignment. If closed reduction is unsuccessful, an open reduction is required, although the timing of said procedure is an area of debate, which we will discuss later.^1,3 Restoration of anatomic carpal alignment is essential to optimizing outcome, although it does not guarantee a good overall result.

Open Reduction

If successful closed reduction is achieved, the patient can be immobilized temporarily in a short-arm plaster splint. However, open reduction and either pinning or internal fixation will be required to maintain this alignment. The exact timing of open reduction and fixation is debatable and often dictated by the absence or presence of median nerve symptoms.^1,3 If a patient with no median nerve symptoms undergoes a successful closed reduction, he or she may be stabilized surgically within 3 to 5 days (or longer) with either pins or headless screws. If closed reduction is unsuccessful, an open reduction should be done within 2 to 3 days. However, if the patient has progressive numbness in the median nerve distribution upon presentation that fails to improve or worsens despite a successful closed reduction, an urgent open reduction (within 24 hours) and carpal tunnel release should be performed to prevent permanent damage to the median nerve.

Once open reduction is undertaken, a dorsal, volar, and combined approach can be used.^2-4 In most cases the dorsal approach is selected first. A longitudinal incision is made over the dorsum of the wrist, centered on the Lister tubercle. Dissection occurs between the third and fourth dorsal compartments. After the capsule is exposed, reduction of the lunate to the capitate is confirmed. If any fractures are present in the carpus (eg, scaphoid), they are internally fixed. The scapholunate articulation is then addressed. In general, the scapholunate ligament is not disrupted with a transscaphoid perilunate dislocation. However, if the scapholunate ligament is disrupted, the joint should be reduced and pinned. Repair or reconstruction of the scapholunate ligament is performed. Finally, the lunotriquetral articulation is reduced and stabilized with pins. There are no studies that specifically suggest direct repair of the lunotriquetral ligament versus pinning of the lunotriquetral articulation, but the lunotriquetral ligament could be repaired in similar fashion to the scapholunate ligament at the surgeon’s discretion.

As an alternative to percutaneous pinning, intercarpal screw fixation can be used to stabilize the carpus. A 2007 study by Souer and colleagues¹² showed no substantial difference in outcome between the 2 methods of fixation. However, a second procedure is required to remove the screws.

The volar approach, if selected, is typically done second and performed via an extended carpal tunnel incision. It allows decompression of the carpal tunnel and enables repair of volar capsular ligaments (ie, long and short radiolunate ligaments, volar scapholunate ligament, and volar lunotriquetral ligament), which increases overall carpal stability. Currently, many surgeons favor a combined dorsal-volar approach for its efficacy.^2,3 Some use a dorsal approach in all patients and perform a volar procedure only if the patient has median nerve symptoms.⁴ However, Başar and colleagues¹³ report use of only the volar approach for treatment of perilunate injuries. The authors repaired the long and short radiolunate ligaments, volar scapholunate ligament, and volar lunotriquetral ligament. They reported reasonably good outcomes, which are equivalent to those reported in similar studies using dorsal or combined dorsal-volar approaches. However, no studies in the literature directly compare any of the different approaches with each other.

Postoperatively, patients are placed in a long-arm thumb-spica cast for 4 weeks, and then in a short-arm cast for 4 to 8 weeks (Figure 2). If present, pins are removed in 3 to 12 weeks, with most authors recommending removal at 8 weeks.^2,14

Lastly, carpal tunnel symptoms can develop late and even after a successful reduction and surgical stabilization. One theory is that a significant perilunate injury can create slightly higher baseline carpal tunnel pressures, which can compromise the blood flow to the median nerve and cause carpal tunnel symptoms. Additionally, it is possible that direct median nerve contusion and/or traction injury via a displaced lunate can also cause these symptoms. Whatever the inciting cause of median-nerve irritation, a delayed carpal tunnel release is sometimes required.

Conclusion

Outcomes after either perilunate or lunate dislocation are fair to good at best but can be optimized with prompt, appropriate treatment. Closed reduction and casting as definitive treatment has been abandoned because of frequent loss of reduction.¹² Early open reduction (ie, less than 3 days after injury) has been shown to be beneficial.^1,2 However, even those treated early and with anatomic restoration of carpal alignment can expect a loss of grip strength and a range of motion of approximately 70% compared with the contralateral side.^2-5 A recent study has suggested that lesser-arc injures generally have a poorer overall outcome than their greater-arc counterparts.¹⁵

More than half of all patients with perilunate injuries will develop radiographic signs of osteoarthritis, and some will require additional salvage procedures.3-5 Kremer and colleagues4 showed that overall results after perilunate injuries deteriorate with time. However, according to a paper by Forli and colleagues5 in which patients were followed a minimum of 10 years after their injuries, the authors found that, despite radiographic progression of arthritis, most patients maintained reasonable hand function.

Perilunate injuries typically stem from a high-energy insult to the carpus. Because of their relative infrequency and often subtle radiographic and physical examination findings, these injuries are often undetected in the emergency department setting.¹ Early anatomic reduction of any carpal malalignment is essential. Even with optimal treatment, complications such as generalized wrist stiffness, diminished grip strength, and posttraumatic arthritis, commonly develop; however, recent studies suggest these issues are often well tolerated.^1-5 In this article, the diagnosis, treatment, and outcomes after perilunate injuries are examined. 

History and Physical Examination

Perilunate injuries result from high-energy trauma to the carpus. Patients with these injuries often present with vague wrist pain and loss of wrist motion. Their fingers are frequently held in slight flexion. The patient may complain of numbness and tingling in the median nerve distribution. An acute carpal tunnel syndrome can rapidly develop. The general belief is that acute carpal tunnel syndrome occurs more commonly in pure volar lunate dislocations than in dorsal perilunate dislocations. However, no studies compare the incidence of acute carpal tunnel syndrome in lunate versus perilunate dislocations.

Radiographic Evaluation

Standard radiographic evaluation of a potential perilunate injury includes posteroanterior (PA), lateral, and oblique views of the wrist (Figure 1). A scaphoid view (ie, PA view with the wrist in ulnar deviation) may also be helpful. The PA view is particularly helpful because it enables assessment of Gilula lines, which are imaginary lines drawn across the proximal and distal aspects of the proximal carpal row and the proximal aspect of the distal carpal row. These lines should appear as 3 smooth arcs running nearly parallel to each other.⁶ Any disruption in these lines suggests carpal incongruity. It may be possible to note a triangular-shaped lunate on the PA view, which is a sign of lunate dislocation.⁷ 

While the PA view is certainly useful, the lateral view is the most important in diagnosing a perilunate injury. The lateral view allows assessment of the collinearity of radius, lunate, and capitate. Any disruption in this collinearity strongly suggests a perilunate dislocation.^7,8 

Classification

Mayfield and colleagues^9,10 described 4 stages of perilunate instability proceeding from a radial to an ulnar direction around the lunate. Stage I involves disruption of the scapholunate joint, while stage II involves both the scapholunate and capitolunate joints. In stage III, the scapholunate, capitolunate, and lunotriquetral ligaments are disrupted, and the result is a perilunate dislocation, usually dorsal. Finally, in stage IV, all the ligaments surrounding the lunate are disrupted and the lunate dislocates, most often volarly.

Lastly, perilunate injuries can be classified as greater-arc injuries if concomitant fracture of the carpus occurs, lesser-arc injuries if the injury is purely ligamentous, or inferior-arc injuries if there is an associated fracture of the volar rim of the distal radius.⁸

Treatment

Closed Reduction

All acute perilunate dislocations should be managed initially with an attempted closed reduction.¹¹ If the injury is older than 72 hours, such an attempt may be futile. For any closed reduction performed in the emergency department setting, intravenous sedation is generally advised for muscle relaxation. Gentle traction with finger traps can also be used prior to the reduction attempt. For a dorsal perilunate dislocation, longitudinal traction followed by volar flexion of the wrist with volar pressure on the lunate and dorsal pressure on the capitate (ie, Tavernier’s maneuver) is required. Once reduction is complete, PA and lateral views of the wrist should be obtained to assess carpal alignment. If closed reduction is unsuccessful, an open reduction is required, although the timing of said procedure is an area of debate, which we will discuss later.^1,3 Restoration of anatomic carpal alignment is essential to optimizing outcome, although it does not guarantee a good overall result.

Open Reduction

If successful closed reduction is achieved, the patient can be immobilized temporarily in a short-arm plaster splint. However, open reduction and either pinning or internal fixation will be required to maintain this alignment. The exact timing of open reduction and fixation is debatable and often dictated by the absence or presence of median nerve symptoms.^1,3 If a patient with no median nerve symptoms undergoes a successful closed reduction, he or she may be stabilized surgically within 3 to 5 days (or longer) with either pins or headless screws. If closed reduction is unsuccessful, an open reduction should be done within 2 to 3 days. However, if the patient has progressive numbness in the median nerve distribution upon presentation that fails to improve or worsens despite a successful closed reduction, an urgent open reduction (within 24 hours) and carpal tunnel release should be performed to prevent permanent damage to the median nerve.

Once open reduction is undertaken, a dorsal, volar, and combined approach can be used.^2-4 In most cases the dorsal approach is selected first. A longitudinal incision is made over the dorsum of the wrist, centered on the Lister tubercle. Dissection occurs between the third and fourth dorsal compartments. After the capsule is exposed, reduction of the lunate to the capitate is confirmed. If any fractures are present in the carpus (eg, scaphoid), they are internally fixed. The scapholunate articulation is then addressed. In general, the scapholunate ligament is not disrupted with a transscaphoid perilunate dislocation. However, if the scapholunate ligament is disrupted, the joint should be reduced and pinned. Repair or reconstruction of the scapholunate ligament is performed. Finally, the lunotriquetral articulation is reduced and stabilized with pins. There are no studies that specifically suggest direct repair of the lunotriquetral ligament versus pinning of the lunotriquetral articulation, but the lunotriquetral ligament could be repaired in similar fashion to the scapholunate ligament at the surgeon’s discretion.

As an alternative to percutaneous pinning, intercarpal screw fixation can be used to stabilize the carpus. A 2007 study by Souer and colleagues¹² showed no substantial difference in outcome between the 2 methods of fixation. However, a second procedure is required to remove the screws.

The volar approach, if selected, is typically done second and performed via an extended carpal tunnel incision. It allows decompression of the carpal tunnel and enables repair of volar capsular ligaments (ie, long and short radiolunate ligaments, volar scapholunate ligament, and volar lunotriquetral ligament), which increases overall carpal stability. Currently, many surgeons favor a combined dorsal-volar approach for its efficacy.^2,3 Some use a dorsal approach in all patients and perform a volar procedure only if the patient has median nerve symptoms.⁴ However, Başar and colleagues¹³ report use of only the volar approach for treatment of perilunate injuries. The authors repaired the long and short radiolunate ligaments, volar scapholunate ligament, and volar lunotriquetral ligament. They reported reasonably good outcomes, which are equivalent to those reported in similar studies using dorsal or combined dorsal-volar approaches. However, no studies in the literature directly compare any of the different approaches with each other.

Postoperatively, patients are placed in a long-arm thumb-spica cast for 4 weeks, and then in a short-arm cast for 4 to 8 weeks (Figure 2). If present, pins are removed in 3 to 12 weeks, with most authors recommending removal at 8 weeks.^2,14

Lastly, carpal tunnel symptoms can develop late and even after a successful reduction and surgical stabilization. One theory is that a significant perilunate injury can create slightly higher baseline carpal tunnel pressures, which can compromise the blood flow to the median nerve and cause carpal tunnel symptoms. Additionally, it is possible that direct median nerve contusion and/or traction injury via a displaced lunate can also cause these symptoms. Whatever the inciting cause of median-nerve irritation, a delayed carpal tunnel release is sometimes required.

Conclusion

Outcomes after either perilunate or lunate dislocation are fair to good at best but can be optimized with prompt, appropriate treatment. Closed reduction and casting as definitive treatment has been abandoned because of frequent loss of reduction.¹² Early open reduction (ie, less than 3 days after injury) has been shown to be beneficial.^1,2 However, even those treated early and with anatomic restoration of carpal alignment can expect a loss of grip strength and a range of motion of approximately 70% compared with the contralateral side.^2-5 A recent study has suggested that lesser-arc injures generally have a poorer overall outcome than their greater-arc counterparts.¹⁵

More than half of all patients with perilunate injuries will develop radiographic signs of osteoarthritis, and some will require additional salvage procedures.3-5 Kremer and colleagues4 showed that overall results after perilunate injuries deteriorate with time. However, according to a paper by Forli and colleagues5 in which patients were followed a minimum of 10 years after their injuries, the authors found that, despite radiographic progression of arthritis, most patients maintained reasonable hand function.

Perilunate injuries typically stem from a high-energy insult to the carpus. Because of their relative infrequency and often subtle radiographic and physical examination findings, these injuries are often undetected in the emergency department setting.¹ Early anatomic reduction of any carpal malalignment is essential. Even with optimal treatment, complications such as generalized wrist stiffness, diminished grip strength, and posttraumatic arthritis, commonly develop; however, recent studies suggest these issues are often well tolerated.^1-5 In this article, the diagnosis, treatment, and outcomes after perilunate injuries are examined. 

History and Physical Examination

Perilunate injuries result from high-energy trauma to the carpus. Patients with these injuries often present with vague wrist pain and loss of wrist motion. Their fingers are frequently held in slight flexion. The patient may complain of numbness and tingling in the median nerve distribution. An acute carpal tunnel syndrome can rapidly develop. The general belief is that acute carpal tunnel syndrome occurs more commonly in pure volar lunate dislocations than in dorsal perilunate dislocations. However, no studies compare the incidence of acute carpal tunnel syndrome in lunate versus perilunate dislocations.

Radiographic Evaluation

Standard radiographic evaluation of a potential perilunate injury includes posteroanterior (PA), lateral, and oblique views of the wrist (Figure 1). A scaphoid view (ie, PA view with the wrist in ulnar deviation) may also be helpful. The PA view is particularly helpful because it enables assessment of Gilula lines, which are imaginary lines drawn across the proximal and distal aspects of the proximal carpal row and the proximal aspect of the distal carpal row. These lines should appear as 3 smooth arcs running nearly parallel to each other.⁶ Any disruption in these lines suggests carpal incongruity. It may be possible to note a triangular-shaped lunate on the PA view, which is a sign of lunate dislocation.⁷ 

While the PA view is certainly useful, the lateral view is the most important in diagnosing a perilunate injury. The lateral view allows assessment of the collinearity of radius, lunate, and capitate. Any disruption in this collinearity strongly suggests a perilunate dislocation.^7,8 

Classification

Mayfield and colleagues^9,10 described 4 stages of perilunate instability proceeding from a radial to an ulnar direction around the lunate. Stage I involves disruption of the scapholunate joint, while stage II involves both the scapholunate and capitolunate joints. In stage III, the scapholunate, capitolunate, and lunotriquetral ligaments are disrupted, and the result is a perilunate dislocation, usually dorsal. Finally, in stage IV, all the ligaments surrounding the lunate are disrupted and the lunate dislocates, most often volarly.

Lastly, perilunate injuries can be classified as greater-arc injuries if concomitant fracture of the carpus occurs, lesser-arc injuries if the injury is purely ligamentous, or inferior-arc injuries if there is an associated fracture of the volar rim of the distal radius.⁸

Treatment

Closed Reduction

All acute perilunate dislocations should be managed initially with an attempted closed reduction.¹¹ If the injury is older than 72 hours, such an attempt may be futile. For any closed reduction performed in the emergency department setting, intravenous sedation is generally advised for muscle relaxation. Gentle traction with finger traps can also be used prior to the reduction attempt. For a dorsal perilunate dislocation, longitudinal traction followed by volar flexion of the wrist with volar pressure on the lunate and dorsal pressure on the capitate (ie, Tavernier’s maneuver) is required. Once reduction is complete, PA and lateral views of the wrist should be obtained to assess carpal alignment. If closed reduction is unsuccessful, an open reduction is required, although the timing of said procedure is an area of debate, which we will discuss later.^1,3 Restoration of anatomic carpal alignment is essential to optimizing outcome, although it does not guarantee a good overall result.

Open Reduction

If successful closed reduction is achieved, the patient can be immobilized temporarily in a short-arm plaster splint. However, open reduction and either pinning or internal fixation will be required to maintain this alignment. The exact timing of open reduction and fixation is debatable and often dictated by the absence or presence of median nerve symptoms.^1,3 If a patient with no median nerve symptoms undergoes a successful closed reduction, he or she may be stabilized surgically within 3 to 5 days (or longer) with either pins or headless screws. If closed reduction is unsuccessful, an open reduction should be done within 2 to 3 days. However, if the patient has progressive numbness in the median nerve distribution upon presentation that fails to improve or worsens despite a successful closed reduction, an urgent open reduction (within 24 hours) and carpal tunnel release should be performed to prevent permanent damage to the median nerve.

Once open reduction is undertaken, a dorsal, volar, and combined approach can be used.^2-4 In most cases the dorsal approach is selected first. A longitudinal incision is made over the dorsum of the wrist, centered on the Lister tubercle. Dissection occurs between the third and fourth dorsal compartments. After the capsule is exposed, reduction of the lunate to the capitate is confirmed. If any fractures are present in the carpus (eg, scaphoid), they are internally fixed. The scapholunate articulation is then addressed. In general, the scapholunate ligament is not disrupted with a transscaphoid perilunate dislocation. However, if the scapholunate ligament is disrupted, the joint should be reduced and pinned. Repair or reconstruction of the scapholunate ligament is performed. Finally, the lunotriquetral articulation is reduced and stabilized with pins. There are no studies that specifically suggest direct repair of the lunotriquetral ligament versus pinning of the lunotriquetral articulation, but the lunotriquetral ligament could be repaired in similar fashion to the scapholunate ligament at the surgeon’s discretion.

As an alternative to percutaneous pinning, intercarpal screw fixation can be used to stabilize the carpus. A 2007 study by Souer and colleagues¹² showed no substantial difference in outcome between the 2 methods of fixation. However, a second procedure is required to remove the screws.

The volar approach, if selected, is typically done second and performed via an extended carpal tunnel incision. It allows decompression of the carpal tunnel and enables repair of volar capsular ligaments (ie, long and short radiolunate ligaments, volar scapholunate ligament, and volar lunotriquetral ligament), which increases overall carpal stability. Currently, many surgeons favor a combined dorsal-volar approach for its efficacy.^2,3 Some use a dorsal approach in all patients and perform a volar procedure only if the patient has median nerve symptoms.⁴ However, Başar and colleagues¹³ report use of only the volar approach for treatment of perilunate injuries. The authors repaired the long and short radiolunate ligaments, volar scapholunate ligament, and volar lunotriquetral ligament. They reported reasonably good outcomes, which are equivalent to those reported in similar studies using dorsal or combined dorsal-volar approaches. However, no studies in the literature directly compare any of the different approaches with each other.

Postoperatively, patients are placed in a long-arm thumb-spica cast for 4 weeks, and then in a short-arm cast for 4 to 8 weeks (Figure 2). If present, pins are removed in 3 to 12 weeks, with most authors recommending removal at 8 weeks.^2,14

Lastly, carpal tunnel symptoms can develop late and even after a successful reduction and surgical stabilization. One theory is that a significant perilunate injury can create slightly higher baseline carpal tunnel pressures, which can compromise the blood flow to the median nerve and cause carpal tunnel symptoms. Additionally, it is possible that direct median nerve contusion and/or traction injury via a displaced lunate can also cause these symptoms. Whatever the inciting cause of median-nerve irritation, a delayed carpal tunnel release is sometimes required.

Conclusion

Outcomes after either perilunate or lunate dislocation are fair to good at best but can be optimized with prompt, appropriate treatment. Closed reduction and casting as definitive treatment has been abandoned because of frequent loss of reduction.¹² Early open reduction (ie, less than 3 days after injury) has been shown to be beneficial.^1,2 However, even those treated early and with anatomic restoration of carpal alignment can expect a loss of grip strength and a range of motion of approximately 70% compared with the contralateral side.^2-5 A recent study has suggested that lesser-arc injures generally have a poorer overall outcome than their greater-arc counterparts.¹⁵

More than half of all patients with perilunate injuries will develop radiographic signs of osteoarthritis, and some will require additional salvage procedures.3-5 Kremer and colleagues4 showed that overall results after perilunate injuries deteriorate with time. However, according to a paper by Forli and colleagues5 in which patients were followed a minimum of 10 years after their injuries, the authors found that, despite radiographic progression of arthritis, most patients maintained reasonable hand function.

A 20-year-old woman with Gaucher disease presents with pain in her right ankle and in her back. She has had the ankle pain for the past 12 months and the back pain for the past 2 years. She describes the ankle pain as stabbing and moderately severe. It is constant, present both at rest and during physical activity, but aggravated by walking and twisting movements. She has noticed grinding and clicking sounds as she moves her ankle. The ankle pain has worsened over the past several months.

She says her back pain is similar to her ankle pain but less severe. She also reports generalized mild aches and bone pain. No other joints are involved. She has no history of fever, chills, or trauma.

A COMPLICATED MEDICAL HISTORY

Her Gaucher disease was diagnosed at age 4 when she presented with failure to thrive and with thrombocytopenia and splenomegaly. She and was found to have an N370S/IVS2+1 mutation of the GBA gene. She underwent removal of 90% of her spleen at the time of diagnosis and was on enzyme replacement therapy with imiglucerase until 3 years ago, when the treatment was stopped because the drug had become unavailable (because of a temporary closure of the manufacturing facility), and because she had developed neutralizing antibodies to it. Despite a dosage as high as 120 U/kg every 2 weeks (the recommended range is 2.5 U/kg three times a week up to 60 U/kg every 2 weeks), her anemia and thrombocytopenia worsened to the point that she became dependent on transfusion of red blood cells and platelets. She has also taken glucocorticoids at various times in the past as a premedication before enzyme replacement therapy.

About 3 years ago, she developed dryness of the skin, pruritus, shiny skin, hardening of the skin, and decreased oral aperture, which was diagnosed as scleroderma.

During the past 5 years, she has had multiple episodes of pale coloration of her skin on exposure to cold, suggestive of Raynaud phenomenon. And for the past 5 months, she has noticed a burning sensation in her throat and retrosternal pain, suggestive of gastroesophageal reflux disease.

She is a college student, with no history of smoking or use of alcohol or recreational drugs. She is sexually active, with no history of sexually transmitted disease, and she uses condoms and oral contraceptives for contraception.

Her father and mother are both carriers of Gaucher disease. She is not of Ashkenazi Jewish descent.

FINDINGS ON PHYSICAL EXAMINATION

On physical examination, her temperature, blood pressure, pulse, and respiratory rate are within normal limits. She has extensive tattooing on her upper chest to hide scarring from previous cannulation ports. The right ankle joint is moderately swollen but shows no other signs of inflammation; its range of motion is limited by severe pain. She has tenderness of the spinous processes and paraspinal area, in addition to multiple tender points in the thoracolumbar area. Palpation of the right hip reveals tenderness of the groin and trochanteric bursa.

No lymphadenopathy, hepatomegaly, splenomegaly, or abdominal masses are noted. Neurologic examination is essentially nonfocal.

Her current medications include omeprazole, ergocalciferol, calcium carbonate, gabapentin, citalopram, and celecoxib. She also takes a multivitamin daily.

1. Which is the most likely underlying cause of her ankle pain?

• Rheumatoid arthritis
• Gaucher disease
• Septic arthritis
• Avascular necrosis secondary to steroid use

Rheumatoid arthritis varies in its presentation. It is usually insidious in onset, migratory, and intermittent, with polyarticular or even monoarticular involvement, and it presents with pain, stiffness, and swelling of the joint.¹ Most often affected are the metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints. Involvement of large joints of the upper and lower limbs is also common.² This is not the most likely cause of this patient’s symptoms, based on the history and the current presentation.

Gaucher disease is a lipidosis caused by accumulation of cellular glycolipids, especially glucocerebrosides, due to deficiency of the enzyme beta-glucosidase. Clinical manifestations include hepatomegaly, splenomegaly, and bone marrow disease presenting as anemia, thrombocytopenia, or skeletal disease.³ Skeletal involvement in Gaucher disease includes bone pain, bone infarcts, and lytic lesions.

Whether splenectomy predisposes the patient to bone manifestations is controversial. Some believe that splenectomy decreases the total body reservoir for the storage of glycolipids and predisposes to their deposition in bone, which in turn results in cortical thinning, impaired remodeling, and decreased intraosseous blood flow, leading to osteonecrosis and fractures.⁴ This is more common in patients with type 1 Gaucher disease who have undergone splenectomy. (Types 2 and 3 are much rarer, occurring mainly in children; central nervous system involvement is a key feature. A discussion of these types is beyond the focus of this paper.) However, some studies suggest that the increase in bone manifestations after splenectomy may be simply because of severe disease.⁵ It should be noted that, since the advent of enzyme replacement therapy for Gaucher disease, splenectomy is now rarely performed.⁶

Anemia is also considered an independent risk factor for the development of avascular necrosis in type 1 Gaucher disease.⁷ Osteonecrosis due to Gaucher disease is relatively common in the femur, tibia, and humerus and uncommon in the ankle joints.⁸

Septic arthritis is unlikely in this patient in the absence of fever or signs of inflammation of the joint. Her long-standing history of ankle pain would also be unusual for infection, but a superimposed infectious process should always be suspected in an arthritic joint.

Avascular necrosis secondary to steroid use. Glucocorticoids are notorious for their adverse effects on bone. They induce osteocyte apoptosis and a decrease in bone remodeling, potentially predisposing to osteonecrosis.⁹ There is a high incidence of osteoporosis, osteonecrosis, and fracture risk with glucocorticoid therapy, and the incidence is dose-dependent. Discontinuation of the drug only partially restores fracture risk to baseline levels.^10,11

A meta-analysis of cohort studies with a total sample size of about 42,000 reported an increased risk of fracture at all ages with the use of glucocorticoids.¹² Because the minimum dosage and duration of therapy to prevent glucocorticoid-induced osteoporosis are not known, the only recommendation is to keep the dosage as low as possible.¹³

Glucocorticoid therapy is the most common cause of nontraumatic avascular necrosis. The risk of osteonecrosis in patients on long-term glucocorticoid therapy may be as high as 40%.¹⁴ The risk is increased with prolonged treatment and with high doses, but it can also occur with short-term exposure to high doses. The increased risk has been shown to persist for as long as 2 years after the drugs are discontinued.¹⁵ Glucocorticoid-induced bone disease commonly affects the hip and vertebrae.

At this stage of the workup, we cannot completely rule out glucocorticoid use as the cause. However, after considering this patient’s presentation and the key features of the other diagnoses, her ankle pain and back pain are more likely caused by her preexisting Gaucher disease.

CONTINUED EVALUATION


Initial laboratory tests (Table 1) reveal severe anemia and thrombocytopenia. Bone marrow biopsy of the iliac crest done as part of the workup for these conditions shows extensive bone marrow space replacement by histiocytic infiltrate, consistent with Gaucher disease. No other marrow process is observed.

Radiography of the ankle (Figure 1) shows a subtle lucency in the talar dome with minimal subarticular collapse seen on the lateral view, suggestive of avascular necrosis and diffuse osteopenia. Joint spaces are maintained.

Magnetic resonance imaging (MRI) of the ankle shows numerous bone infarcts with an approximately 15-mm region of mild articular surface collapse in the central and lateral aspect of the talar dome.

MRI of the back shows extensive abnormal bone marrow signal intensity throughout the spine, compatible with a marrow replacement process. Patchy nonexpansile T2/stir hyperintensity with serpiginous enhancement within the T9, T11, T12, L2, and L3 vertebral bodies as well as throughout the entire sacrum is consistent with bone infarct.

2. Based on the results of radiographic studies, which is most likely the immediate cause of her ankle pain?

• Talar avascular necrosis secondary to rheumatoid arthritis
• Talar avascular necrosis secondary to Gaucher disease
• Trauma-induced fracture of the talus
• Plantar fasciitis

Of the bones of the feet, the talus is unique. It is the second largest of the tarsal bones and does not have muscular or tendinous attachments. Sixty percent of the talus bone is covered by articular cartilage,¹⁶ so only a limited area is available for penetration of blood vessels. Also, small nutrient vessels and variations of intraosseous anastomoses with a lack of collateral circulation predispose the talus to osteonecrosis when the vascular supply is compromised.¹⁶

Radiographic evidence of avascular necrosis is the presence of bone that is more radiopaque than normal bone; this is necrotic bone surrounded by osteopenic bone. Avascular necrosis causes hyperemia and resorption of bone. The resorption does not take place in necrotic bone because of the lack of a vascular supply, and so it appears radiopaque, whereas the bone surrounding the necrotic bone becomes osteopenic and radiolucent.

The sclerotic rim of a bone infarct is also enhanced by an attempted healing process in which new bone forms on the surface of necrotic trabeculae, a process known as “creeping substitution.” This gives a typical sclerotic picture of the talus.

MRI is the most sensitive technique for detecting osteonecrosis. A characteristic radiographic pattern is seen with osteonecrosis of the talus starting with talar dome opacity, followed by deformity and, in severe cases, articular collapse and bone fragmentation.¹⁷

The radiograph in our patient’s case is not consistent with features of rheumatoid arthritis or traumatic fracture of the talus. In plantar fasciitis, radiographs are used to rule out other pathologies of the foot, and the only finding may be a bone spur seen at the site of pain. The bone spur is not the cause of pain in plantar fasciitis but may be a result of the plantar fasciitis itself.

Therefore, avascular necrosis secondary to Gaucher disease is most likely the immediate cause of her ankle pain.

THE COURSE OF TREATMENT

The patient is started on enzyme replacement therapy with taliglucerase alfa (see discussion of enzyme replacement below). For the ankle pain, conservative management is prescribed, with application of a splint and a boot.

After 4 months of conservative management, radiography (Figure 2) and magnetic resonance imaging (Figure 3) show progressive deterioration of the talus body, and her ankle pain has worsened. A 6-week trial of an ankle brace also proves futile. Her pain continues to worsen and is not controllable with high doses of pain medication. She requests below-the-knee amputation.

Given the complexity of this patient’s medical condition, fusion of the ankle and hindfoot—which in some patients is preferable to amputation—is not considered because of her extensive bone involvement and ongoing thrombocytopenia, which would impede healing after the procedure. Below-the-knee amputation is performed without complications.

Study of the specimen after amputation reveals talar bone necrosis and bone marrow infiltration by foamy macrophages, consistent with Gaucher disease (Figures 4–6).

GAUCHER DISEASE

Pharmacologic treatments, effective only for type 1 Gaucher disease, target hepatosplenomegaly, cytopenia, and bone manifestations. Two approaches are enzyme replacement therapy—ie, to replace the defective enzyme—and substrate reduction therapy—ie, to reduce the production and thus the accumulation of glucocerebroside. Enzyme replacement is the first choice of therapy; substrate reduction is reserved for patients unable to tolerate enzyme replacement therapy.

Enzyme replacement

Current drugs for enzyme replacement therapy are imiglucerase, taliglucerase alfa, and velaglucerase alfa. The drugs are given by intravenous infusion over 1 to 2 hours in an outpatient clinic or office every 2 weeks.

These drugs are extremely expensive. Currently, the estimated cost of therapy for 1 year would be $432,978 for imiglucerase, $324,870 for taliglucerase alfa, and $368,550 for velaglucerase alfa. (The estimated costs are for 1 year of treatment for a 70-kg patient at 60 U/kg every 2 weeks.)¹⁸ Taliglucerase alfa is less expensive than the other two because it is plant-derived and thus can be more readily produced on a large scale.¹⁹

Substrate reduction

Current drugs for substrate reduction therapy are eliglustat and miglustat. They are given orally. Eliglustat is the first oral drug approved as a first-line treatment for Gaucher disease.²⁰ Miglustat is approved only for mild to moderate disease when enzyme replacement fails or is not tolerated.

Patients can develop antibodies to any of the enzyme replacement drugs. It is not known whether this antibody response differs among the three drugs.²¹

Avascular necrosis of bone can occur in many clinical settings especially after a fracture, particularly of the head of the femur, which leads to interruption of blood supply to the area. Patients with sickle cell disease, those on corticosteroids or bisphosphonates (the latter causing osteonecrosis of the jaw), and those who have pancreatitis or human immunodeficiency virus infection are more prone to this bone complication.

In Gaucher disease, osteonecrosis is associated with splenectomy and severe disease and tends to occur at a younger age than in patients with other diagnoses.⁸ The plasma chitotriosidase activity and pulmonary and activation-regulated chemokines (PARC/CCL18), which are 10 to 40 times higher than normal in symptomatic patients with Gaucher disease, can be used as a biomarker of disease activity.⁸ Only plasma chitotriosidase is clinically available and used on a routine basis.

Bone involvement is seen in approximately 75% of the patients with type 1 Gaucher disease,²² and osteonecrosis is a severe form of bone involvement. Monitoring of patients for bone involvement is recommended. Enzyme replacement therapy for Gaucher disease needs to be started even if visceral disease is absent if the patient has evidence of bone involvement in the form of avascular necrosis.⁷ Prospective studies have shown that enzyme replacement therapy reduces the incidence of osteonecrosis.²³

FOLLOW-UP MANAGEMENT OF OUR PATIENT

Avascular necrosis in Gaucher disease more typically involves the hips and shoulders. In the case of our patient, the talus was the most affected bone. Other contributing factors may have been the use of steroids as a premedication (often unnecessary) for her enzyme replacement therapy, as well as the coexistent scleroderma.²⁴

The decision to switch from imiglucerase, to which she developed antibodies, to taliglucerase was made in the hope that the antibodies would not cross-react. After she started taliglucerase, her complete blood count values improved steadily. She did not require transfusions for more than 1 year. Her platelet count rose to 90 × 10⁹/L, and her hemoglobin to 12 g/dL.

A multidisciplinary approach with regular monitoring and appropriate initiation of therapy is necessary to prevent disastrous complications in patients with Gaucher disease.

A 20-year-old woman with Gaucher disease presents with pain in her right ankle and in her back. She has had the ankle pain for the past 12 months and the back pain for the past 2 years. She describes the ankle pain as stabbing and moderately severe. It is constant, present both at rest and during physical activity, but aggravated by walking and twisting movements. She has noticed grinding and clicking sounds as she moves her ankle. The ankle pain has worsened over the past several months.

She says her back pain is similar to her ankle pain but less severe. She also reports generalized mild aches and bone pain. No other joints are involved. She has no history of fever, chills, or trauma.

A COMPLICATED MEDICAL HISTORY

Her Gaucher disease was diagnosed at age 4 when she presented with failure to thrive and with thrombocytopenia and splenomegaly. She and was found to have an N370S/IVS2+1 mutation of the GBA gene. She underwent removal of 90% of her spleen at the time of diagnosis and was on enzyme replacement therapy with imiglucerase until 3 years ago, when the treatment was stopped because the drug had become unavailable (because of a temporary closure of the manufacturing facility), and because she had developed neutralizing antibodies to it. Despite a dosage as high as 120 U/kg every 2 weeks (the recommended range is 2.5 U/kg three times a week up to 60 U/kg every 2 weeks), her anemia and thrombocytopenia worsened to the point that she became dependent on transfusion of red blood cells and platelets. She has also taken glucocorticoids at various times in the past as a premedication before enzyme replacement therapy.

About 3 years ago, she developed dryness of the skin, pruritus, shiny skin, hardening of the skin, and decreased oral aperture, which was diagnosed as scleroderma.

During the past 5 years, she has had multiple episodes of pale coloration of her skin on exposure to cold, suggestive of Raynaud phenomenon. And for the past 5 months, she has noticed a burning sensation in her throat and retrosternal pain, suggestive of gastroesophageal reflux disease.

She is a college student, with no history of smoking or use of alcohol or recreational drugs. She is sexually active, with no history of sexually transmitted disease, and she uses condoms and oral contraceptives for contraception.

Her father and mother are both carriers of Gaucher disease. She is not of Ashkenazi Jewish descent.

FINDINGS ON PHYSICAL EXAMINATION

On physical examination, her temperature, blood pressure, pulse, and respiratory rate are within normal limits. She has extensive tattooing on her upper chest to hide scarring from previous cannulation ports. The right ankle joint is moderately swollen but shows no other signs of inflammation; its range of motion is limited by severe pain. She has tenderness of the spinous processes and paraspinal area, in addition to multiple tender points in the thoracolumbar area. Palpation of the right hip reveals tenderness of the groin and trochanteric bursa.

No lymphadenopathy, hepatomegaly, splenomegaly, or abdominal masses are noted. Neurologic examination is essentially nonfocal.

Her current medications include omeprazole, ergocalciferol, calcium carbonate, gabapentin, citalopram, and celecoxib. She also takes a multivitamin daily.

1. Which is the most likely underlying cause of her ankle pain?

• Rheumatoid arthritis
• Gaucher disease
• Septic arthritis
• Avascular necrosis secondary to steroid use

Rheumatoid arthritis varies in its presentation. It is usually insidious in onset, migratory, and intermittent, with polyarticular or even monoarticular involvement, and it presents with pain, stiffness, and swelling of the joint.¹ Most often affected are the metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints. Involvement of large joints of the upper and lower limbs is also common.² This is not the most likely cause of this patient’s symptoms, based on the history and the current presentation.

Gaucher disease is a lipidosis caused by accumulation of cellular glycolipids, especially glucocerebrosides, due to deficiency of the enzyme beta-glucosidase. Clinical manifestations include hepatomegaly, splenomegaly, and bone marrow disease presenting as anemia, thrombocytopenia, or skeletal disease.³ Skeletal involvement in Gaucher disease includes bone pain, bone infarcts, and lytic lesions.

Whether splenectomy predisposes the patient to bone manifestations is controversial. Some believe that splenectomy decreases the total body reservoir for the storage of glycolipids and predisposes to their deposition in bone, which in turn results in cortical thinning, impaired remodeling, and decreased intraosseous blood flow, leading to osteonecrosis and fractures.⁴ This is more common in patients with type 1 Gaucher disease who have undergone splenectomy. (Types 2 and 3 are much rarer, occurring mainly in children; central nervous system involvement is a key feature. A discussion of these types is beyond the focus of this paper.) However, some studies suggest that the increase in bone manifestations after splenectomy may be simply because of severe disease.⁵ It should be noted that, since the advent of enzyme replacement therapy for Gaucher disease, splenectomy is now rarely performed.⁶

Anemia is also considered an independent risk factor for the development of avascular necrosis in type 1 Gaucher disease.⁷ Osteonecrosis due to Gaucher disease is relatively common in the femur, tibia, and humerus and uncommon in the ankle joints.⁸

Septic arthritis is unlikely in this patient in the absence of fever or signs of inflammation of the joint. Her long-standing history of ankle pain would also be unusual for infection, but a superimposed infectious process should always be suspected in an arthritic joint.

Avascular necrosis secondary to steroid use. Glucocorticoids are notorious for their adverse effects on bone. They induce osteocyte apoptosis and a decrease in bone remodeling, potentially predisposing to osteonecrosis.⁹ There is a high incidence of osteoporosis, osteonecrosis, and fracture risk with glucocorticoid therapy, and the incidence is dose-dependent. Discontinuation of the drug only partially restores fracture risk to baseline levels.^10,11

A meta-analysis of cohort studies with a total sample size of about 42,000 reported an increased risk of fracture at all ages with the use of glucocorticoids.¹² Because the minimum dosage and duration of therapy to prevent glucocorticoid-induced osteoporosis are not known, the only recommendation is to keep the dosage as low as possible.¹³

Glucocorticoid therapy is the most common cause of nontraumatic avascular necrosis. The risk of osteonecrosis in patients on long-term glucocorticoid therapy may be as high as 40%.¹⁴ The risk is increased with prolonged treatment and with high doses, but it can also occur with short-term exposure to high doses. The increased risk has been shown to persist for as long as 2 years after the drugs are discontinued.¹⁵ Glucocorticoid-induced bone disease commonly affects the hip and vertebrae.

At this stage of the workup, we cannot completely rule out glucocorticoid use as the cause. However, after considering this patient’s presentation and the key features of the other diagnoses, her ankle pain and back pain are more likely caused by her preexisting Gaucher disease.

CONTINUED EVALUATION


Initial laboratory tests (Table 1) reveal severe anemia and thrombocytopenia. Bone marrow biopsy of the iliac crest done as part of the workup for these conditions shows extensive bone marrow space replacement by histiocytic infiltrate, consistent with Gaucher disease. No other marrow process is observed.

Radiography of the ankle (Figure 1) shows a subtle lucency in the talar dome with minimal subarticular collapse seen on the lateral view, suggestive of avascular necrosis and diffuse osteopenia. Joint spaces are maintained.

Magnetic resonance imaging (MRI) of the ankle shows numerous bone infarcts with an approximately 15-mm region of mild articular surface collapse in the central and lateral aspect of the talar dome.

MRI of the back shows extensive abnormal bone marrow signal intensity throughout the spine, compatible with a marrow replacement process. Patchy nonexpansile T2/stir hyperintensity with serpiginous enhancement within the T9, T11, T12, L2, and L3 vertebral bodies as well as throughout the entire sacrum is consistent with bone infarct.

2. Based on the results of radiographic studies, which is most likely the immediate cause of her ankle pain?

• Talar avascular necrosis secondary to rheumatoid arthritis
• Talar avascular necrosis secondary to Gaucher disease
• Trauma-induced fracture of the talus
• Plantar fasciitis

Of the bones of the feet, the talus is unique. It is the second largest of the tarsal bones and does not have muscular or tendinous attachments. Sixty percent of the talus bone is covered by articular cartilage,¹⁶ so only a limited area is available for penetration of blood vessels. Also, small nutrient vessels and variations of intraosseous anastomoses with a lack of collateral circulation predispose the talus to osteonecrosis when the vascular supply is compromised.¹⁶

Radiographic evidence of avascular necrosis is the presence of bone that is more radiopaque than normal bone; this is necrotic bone surrounded by osteopenic bone. Avascular necrosis causes hyperemia and resorption of bone. The resorption does not take place in necrotic bone because of the lack of a vascular supply, and so it appears radiopaque, whereas the bone surrounding the necrotic bone becomes osteopenic and radiolucent.

The sclerotic rim of a bone infarct is also enhanced by an attempted healing process in which new bone forms on the surface of necrotic trabeculae, a process known as “creeping substitution.” This gives a typical sclerotic picture of the talus.

MRI is the most sensitive technique for detecting osteonecrosis. A characteristic radiographic pattern is seen with osteonecrosis of the talus starting with talar dome opacity, followed by deformity and, in severe cases, articular collapse and bone fragmentation.¹⁷

The radiograph in our patient’s case is not consistent with features of rheumatoid arthritis or traumatic fracture of the talus. In plantar fasciitis, radiographs are used to rule out other pathologies of the foot, and the only finding may be a bone spur seen at the site of pain. The bone spur is not the cause of pain in plantar fasciitis but may be a result of the plantar fasciitis itself.

Therefore, avascular necrosis secondary to Gaucher disease is most likely the immediate cause of her ankle pain.

THE COURSE OF TREATMENT

The patient is started on enzyme replacement therapy with taliglucerase alfa (see discussion of enzyme replacement below). For the ankle pain, conservative management is prescribed, with application of a splint and a boot.

After 4 months of conservative management, radiography (Figure 2) and magnetic resonance imaging (Figure 3) show progressive deterioration of the talus body, and her ankle pain has worsened. A 6-week trial of an ankle brace also proves futile. Her pain continues to worsen and is not controllable with high doses of pain medication. She requests below-the-knee amputation.

Given the complexity of this patient’s medical condition, fusion of the ankle and hindfoot—which in some patients is preferable to amputation—is not considered because of her extensive bone involvement and ongoing thrombocytopenia, which would impede healing after the procedure. Below-the-knee amputation is performed without complications.

Study of the specimen after amputation reveals talar bone necrosis and bone marrow infiltration by foamy macrophages, consistent with Gaucher disease (Figures 4–6).

GAUCHER DISEASE

Pharmacologic treatments, effective only for type 1 Gaucher disease, target hepatosplenomegaly, cytopenia, and bone manifestations. Two approaches are enzyme replacement therapy—ie, to replace the defective enzyme—and substrate reduction therapy—ie, to reduce the production and thus the accumulation of glucocerebroside. Enzyme replacement is the first choice of therapy; substrate reduction is reserved for patients unable to tolerate enzyme replacement therapy.

Enzyme replacement

Current drugs for enzyme replacement therapy are imiglucerase, taliglucerase alfa, and velaglucerase alfa. The drugs are given by intravenous infusion over 1 to 2 hours in an outpatient clinic or office every 2 weeks.

These drugs are extremely expensive. Currently, the estimated cost of therapy for 1 year would be $432,978 for imiglucerase, $324,870 for taliglucerase alfa, and $368,550 for velaglucerase alfa. (The estimated costs are for 1 year of treatment for a 70-kg patient at 60 U/kg every 2 weeks.)¹⁸ Taliglucerase alfa is less expensive than the other two because it is plant-derived and thus can be more readily produced on a large scale.¹⁹

Substrate reduction

Current drugs for substrate reduction therapy are eliglustat and miglustat. They are given orally. Eliglustat is the first oral drug approved as a first-line treatment for Gaucher disease.²⁰ Miglustat is approved only for mild to moderate disease when enzyme replacement fails or is not tolerated.

Patients can develop antibodies to any of the enzyme replacement drugs. It is not known whether this antibody response differs among the three drugs.²¹

Avascular necrosis of bone can occur in many clinical settings especially after a fracture, particularly of the head of the femur, which leads to interruption of blood supply to the area. Patients with sickle cell disease, those on corticosteroids or bisphosphonates (the latter causing osteonecrosis of the jaw), and those who have pancreatitis or human immunodeficiency virus infection are more prone to this bone complication.

In Gaucher disease, osteonecrosis is associated with splenectomy and severe disease and tends to occur at a younger age than in patients with other diagnoses.⁸ The plasma chitotriosidase activity and pulmonary and activation-regulated chemokines (PARC/CCL18), which are 10 to 40 times higher than normal in symptomatic patients with Gaucher disease, can be used as a biomarker of disease activity.⁸ Only plasma chitotriosidase is clinically available and used on a routine basis.

Bone involvement is seen in approximately 75% of the patients with type 1 Gaucher disease,²² and osteonecrosis is a severe form of bone involvement. Monitoring of patients for bone involvement is recommended. Enzyme replacement therapy for Gaucher disease needs to be started even if visceral disease is absent if the patient has evidence of bone involvement in the form of avascular necrosis.⁷ Prospective studies have shown that enzyme replacement therapy reduces the incidence of osteonecrosis.²³

FOLLOW-UP MANAGEMENT OF OUR PATIENT

Avascular necrosis in Gaucher disease more typically involves the hips and shoulders. In the case of our patient, the talus was the most affected bone. Other contributing factors may have been the use of steroids as a premedication (often unnecessary) for her enzyme replacement therapy, as well as the coexistent scleroderma.²⁴

The decision to switch from imiglucerase, to which she developed antibodies, to taliglucerase was made in the hope that the antibodies would not cross-react. After she started taliglucerase, her complete blood count values improved steadily. She did not require transfusions for more than 1 year. Her platelet count rose to 90 × 10⁹/L, and her hemoglobin to 12 g/dL.

A multidisciplinary approach with regular monitoring and appropriate initiation of therapy is necessary to prevent disastrous complications in patients with Gaucher disease.

A 20-year-old woman with Gaucher disease presents with pain in her right ankle and in her back. She has had the ankle pain for the past 12 months and the back pain for the past 2 years. She describes the ankle pain as stabbing and moderately severe. It is constant, present both at rest and during physical activity, but aggravated by walking and twisting movements. She has noticed grinding and clicking sounds as she moves her ankle. The ankle pain has worsened over the past several months.

She says her back pain is similar to her ankle pain but less severe. She also reports generalized mild aches and bone pain. No other joints are involved. She has no history of fever, chills, or trauma.

A COMPLICATED MEDICAL HISTORY

Her Gaucher disease was diagnosed at age 4 when she presented with failure to thrive and with thrombocytopenia and splenomegaly. She and was found to have an N370S/IVS2+1 mutation of the GBA gene. She underwent removal of 90% of her spleen at the time of diagnosis and was on enzyme replacement therapy with imiglucerase until 3 years ago, when the treatment was stopped because the drug had become unavailable (because of a temporary closure of the manufacturing facility), and because she had developed neutralizing antibodies to it. Despite a dosage as high as 120 U/kg every 2 weeks (the recommended range is 2.5 U/kg three times a week up to 60 U/kg every 2 weeks), her anemia and thrombocytopenia worsened to the point that she became dependent on transfusion of red blood cells and platelets. She has also taken glucocorticoids at various times in the past as a premedication before enzyme replacement therapy.

About 3 years ago, she developed dryness of the skin, pruritus, shiny skin, hardening of the skin, and decreased oral aperture, which was diagnosed as scleroderma.

During the past 5 years, she has had multiple episodes of pale coloration of her skin on exposure to cold, suggestive of Raynaud phenomenon. And for the past 5 months, she has noticed a burning sensation in her throat and retrosternal pain, suggestive of gastroesophageal reflux disease.

She is a college student, with no history of smoking or use of alcohol or recreational drugs. She is sexually active, with no history of sexually transmitted disease, and she uses condoms and oral contraceptives for contraception.

Her father and mother are both carriers of Gaucher disease. She is not of Ashkenazi Jewish descent.

FINDINGS ON PHYSICAL EXAMINATION

On physical examination, her temperature, blood pressure, pulse, and respiratory rate are within normal limits. She has extensive tattooing on her upper chest to hide scarring from previous cannulation ports. The right ankle joint is moderately swollen but shows no other signs of inflammation; its range of motion is limited by severe pain. She has tenderness of the spinous processes and paraspinal area, in addition to multiple tender points in the thoracolumbar area. Palpation of the right hip reveals tenderness of the groin and trochanteric bursa.

No lymphadenopathy, hepatomegaly, splenomegaly, or abdominal masses are noted. Neurologic examination is essentially nonfocal.

Her current medications include omeprazole, ergocalciferol, calcium carbonate, gabapentin, citalopram, and celecoxib. She also takes a multivitamin daily.

1. Which is the most likely underlying cause of her ankle pain?

• Rheumatoid arthritis
• Gaucher disease
• Septic arthritis
• Avascular necrosis secondary to steroid use

Rheumatoid arthritis varies in its presentation. It is usually insidious in onset, migratory, and intermittent, with polyarticular or even monoarticular involvement, and it presents with pain, stiffness, and swelling of the joint.¹ Most often affected are the metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints. Involvement of large joints of the upper and lower limbs is also common.² This is not the most likely cause of this patient’s symptoms, based on the history and the current presentation.

Gaucher disease is a lipidosis caused by accumulation of cellular glycolipids, especially glucocerebrosides, due to deficiency of the enzyme beta-glucosidase. Clinical manifestations include hepatomegaly, splenomegaly, and bone marrow disease presenting as anemia, thrombocytopenia, or skeletal disease.³ Skeletal involvement in Gaucher disease includes bone pain, bone infarcts, and lytic lesions.

Whether splenectomy predisposes the patient to bone manifestations is controversial. Some believe that splenectomy decreases the total body reservoir for the storage of glycolipids and predisposes to their deposition in bone, which in turn results in cortical thinning, impaired remodeling, and decreased intraosseous blood flow, leading to osteonecrosis and fractures.⁴ This is more common in patients with type 1 Gaucher disease who have undergone splenectomy. (Types 2 and 3 are much rarer, occurring mainly in children; central nervous system involvement is a key feature. A discussion of these types is beyond the focus of this paper.) However, some studies suggest that the increase in bone manifestations after splenectomy may be simply because of severe disease.⁵ It should be noted that, since the advent of enzyme replacement therapy for Gaucher disease, splenectomy is now rarely performed.⁶

Anemia is also considered an independent risk factor for the development of avascular necrosis in type 1 Gaucher disease.⁷ Osteonecrosis due to Gaucher disease is relatively common in the femur, tibia, and humerus and uncommon in the ankle joints.⁸

Septic arthritis is unlikely in this patient in the absence of fever or signs of inflammation of the joint. Her long-standing history of ankle pain would also be unusual for infection, but a superimposed infectious process should always be suspected in an arthritic joint.

Avascular necrosis secondary to steroid use. Glucocorticoids are notorious for their adverse effects on bone. They induce osteocyte apoptosis and a decrease in bone remodeling, potentially predisposing to osteonecrosis.⁹ There is a high incidence of osteoporosis, osteonecrosis, and fracture risk with glucocorticoid therapy, and the incidence is dose-dependent. Discontinuation of the drug only partially restores fracture risk to baseline levels.^10,11

A meta-analysis of cohort studies with a total sample size of about 42,000 reported an increased risk of fracture at all ages with the use of glucocorticoids.¹² Because the minimum dosage and duration of therapy to prevent glucocorticoid-induced osteoporosis are not known, the only recommendation is to keep the dosage as low as possible.¹³

Glucocorticoid therapy is the most common cause of nontraumatic avascular necrosis. The risk of osteonecrosis in patients on long-term glucocorticoid therapy may be as high as 40%.¹⁴ The risk is increased with prolonged treatment and with high doses, but it can also occur with short-term exposure to high doses. The increased risk has been shown to persist for as long as 2 years after the drugs are discontinued.¹⁵ Glucocorticoid-induced bone disease commonly affects the hip and vertebrae.

At this stage of the workup, we cannot completely rule out glucocorticoid use as the cause. However, after considering this patient’s presentation and the key features of the other diagnoses, her ankle pain and back pain are more likely caused by her preexisting Gaucher disease.

CONTINUED EVALUATION


Initial laboratory tests (Table 1) reveal severe anemia and thrombocytopenia. Bone marrow biopsy of the iliac crest done as part of the workup for these conditions shows extensive bone marrow space replacement by histiocytic infiltrate, consistent with Gaucher disease. No other marrow process is observed.

Radiography of the ankle (Figure 1) shows a subtle lucency in the talar dome with minimal subarticular collapse seen on the lateral view, suggestive of avascular necrosis and diffuse osteopenia. Joint spaces are maintained.

Magnetic resonance imaging (MRI) of the ankle shows numerous bone infarcts with an approximately 15-mm region of mild articular surface collapse in the central and lateral aspect of the talar dome.

MRI of the back shows extensive abnormal bone marrow signal intensity throughout the spine, compatible with a marrow replacement process. Patchy nonexpansile T2/stir hyperintensity with serpiginous enhancement within the T9, T11, T12, L2, and L3 vertebral bodies as well as throughout the entire sacrum is consistent with bone infarct.

2. Based on the results of radiographic studies, which is most likely the immediate cause of her ankle pain?

• Talar avascular necrosis secondary to rheumatoid arthritis
• Talar avascular necrosis secondary to Gaucher disease
• Trauma-induced fracture of the talus
• Plantar fasciitis

Of the bones of the feet, the talus is unique. It is the second largest of the tarsal bones and does not have muscular or tendinous attachments. Sixty percent of the talus bone is covered by articular cartilage,¹⁶ so only a limited area is available for penetration of blood vessels. Also, small nutrient vessels and variations of intraosseous anastomoses with a lack of collateral circulation predispose the talus to osteonecrosis when the vascular supply is compromised.¹⁶

Radiographic evidence of avascular necrosis is the presence of bone that is more radiopaque than normal bone; this is necrotic bone surrounded by osteopenic bone. Avascular necrosis causes hyperemia and resorption of bone. The resorption does not take place in necrotic bone because of the lack of a vascular supply, and so it appears radiopaque, whereas the bone surrounding the necrotic bone becomes osteopenic and radiolucent.

The sclerotic rim of a bone infarct is also enhanced by an attempted healing process in which new bone forms on the surface of necrotic trabeculae, a process known as “creeping substitution.” This gives a typical sclerotic picture of the talus.

MRI is the most sensitive technique for detecting osteonecrosis. A characteristic radiographic pattern is seen with osteonecrosis of the talus starting with talar dome opacity, followed by deformity and, in severe cases, articular collapse and bone fragmentation.¹⁷

The radiograph in our patient’s case is not consistent with features of rheumatoid arthritis or traumatic fracture of the talus. In plantar fasciitis, radiographs are used to rule out other pathologies of the foot, and the only finding may be a bone spur seen at the site of pain. The bone spur is not the cause of pain in plantar fasciitis but may be a result of the plantar fasciitis itself.

Therefore, avascular necrosis secondary to Gaucher disease is most likely the immediate cause of her ankle pain.

THE COURSE OF TREATMENT

The patient is started on enzyme replacement therapy with taliglucerase alfa (see discussion of enzyme replacement below). For the ankle pain, conservative management is prescribed, with application of a splint and a boot.

After 4 months of conservative management, radiography (Figure 2) and magnetic resonance imaging (Figure 3) show progressive deterioration of the talus body, and her ankle pain has worsened. A 6-week trial of an ankle brace also proves futile. Her pain continues to worsen and is not controllable with high doses of pain medication. She requests below-the-knee amputation.

Given the complexity of this patient’s medical condition, fusion of the ankle and hindfoot—which in some patients is preferable to amputation—is not considered because of her extensive bone involvement and ongoing thrombocytopenia, which would impede healing after the procedure. Below-the-knee amputation is performed without complications.

Study of the specimen after amputation reveals talar bone necrosis and bone marrow infiltration by foamy macrophages, consistent with Gaucher disease (Figures 4–6).

GAUCHER DISEASE

Pharmacologic treatments, effective only for type 1 Gaucher disease, target hepatosplenomegaly, cytopenia, and bone manifestations. Two approaches are enzyme replacement therapy—ie, to replace the defective enzyme—and substrate reduction therapy—ie, to reduce the production and thus the accumulation of glucocerebroside. Enzyme replacement is the first choice of therapy; substrate reduction is reserved for patients unable to tolerate enzyme replacement therapy.

Enzyme replacement

Current drugs for enzyme replacement therapy are imiglucerase, taliglucerase alfa, and velaglucerase alfa. The drugs are given by intravenous infusion over 1 to 2 hours in an outpatient clinic or office every 2 weeks.

These drugs are extremely expensive. Currently, the estimated cost of therapy for 1 year would be $432,978 for imiglucerase, $324,870 for taliglucerase alfa, and $368,550 for velaglucerase alfa. (The estimated costs are for 1 year of treatment for a 70-kg patient at 60 U/kg every 2 weeks.)¹⁸ Taliglucerase alfa is less expensive than the other two because it is plant-derived and thus can be more readily produced on a large scale.¹⁹

Substrate reduction

Current drugs for substrate reduction therapy are eliglustat and miglustat. They are given orally. Eliglustat is the first oral drug approved as a first-line treatment for Gaucher disease.²⁰ Miglustat is approved only for mild to moderate disease when enzyme replacement fails or is not tolerated.

Patients can develop antibodies to any of the enzyme replacement drugs. It is not known whether this antibody response differs among the three drugs.²¹

Avascular necrosis of bone can occur in many clinical settings especially after a fracture, particularly of the head of the femur, which leads to interruption of blood supply to the area. Patients with sickle cell disease, those on corticosteroids or bisphosphonates (the latter causing osteonecrosis of the jaw), and those who have pancreatitis or human immunodeficiency virus infection are more prone to this bone complication.

In Gaucher disease, osteonecrosis is associated with splenectomy and severe disease and tends to occur at a younger age than in patients with other diagnoses.⁸ The plasma chitotriosidase activity and pulmonary and activation-regulated chemokines (PARC/CCL18), which are 10 to 40 times higher than normal in symptomatic patients with Gaucher disease, can be used as a biomarker of disease activity.⁸ Only plasma chitotriosidase is clinically available and used on a routine basis.

Bone involvement is seen in approximately 75% of the patients with type 1 Gaucher disease,²² and osteonecrosis is a severe form of bone involvement. Monitoring of patients for bone involvement is recommended. Enzyme replacement therapy for Gaucher disease needs to be started even if visceral disease is absent if the patient has evidence of bone involvement in the form of avascular necrosis.⁷ Prospective studies have shown that enzyme replacement therapy reduces the incidence of osteonecrosis.²³

FOLLOW-UP MANAGEMENT OF OUR PATIENT

Avascular necrosis in Gaucher disease more typically involves the hips and shoulders. In the case of our patient, the talus was the most affected bone. Other contributing factors may have been the use of steroids as a premedication (often unnecessary) for her enzyme replacement therapy, as well as the coexistent scleroderma.²⁴

The decision to switch from imiglucerase, to which she developed antibodies, to taliglucerase was made in the hope that the antibodies would not cross-react. After she started taliglucerase, her complete blood count values improved steadily. She did not require transfusions for more than 1 year. Her platelet count rose to 90 × 10⁹/L, and her hemoglobin to 12 g/dL.

A multidisciplinary approach with regular monitoring and appropriate initiation of therapy is necessary to prevent disastrous complications in patients with Gaucher disease.

This has been a boom year for Parkinson disease, with the US Food and Drug Administration (FDA) approving two new therapies, and with others in the pipeline.

This article details clinical signs of Parkinson disease, discusses functional imaging, provides an update on current thinking on disease pathogenesis, and gives an overview of managing parkinsonian symptoms and dyskinesias.

DIAGNOSIS REMAINS CLINICAL

Although a better understanding of Parkinson disease has been gained in recent years, with the recognition of several premotor features and potential biomarkers, its diagnosis is still primarily based on clinical motor findings. The four cardinal motor features have the mnemonic TRAP:

• Tremor at rest can be subtle, involving just the thumb, best observed when the patient is sitting with the hand resting on the lap; or it can be obvious, involving the entire hand, arm, feet, lips, and chin.
• Rigidity can be felt rather than seen, by slowly passively rotating the patient’s wrist or elbow and feeling resistance. The right and left sides often differ.
• Akinesia or bradykinesia (slowness or lack of movement) can be observed by having the patient walk down a hallway. One may observe reduced arm swing and hesitation in initiating movement.
• Postural instability usually develops later rather than sooner in the disease progression. The patient may need to hold onto someone to maintain balance when getting up or walking.

At least two features must be present to make the diagnosis of parkinsonism. One feature must be tremor or rigidity.

The TRAP features of Parkinson disease:
• Tremor
• Rigidity
• Akinesia
• Postural instabilityAlthough the criteria for parkinsonism appear simple, the diagnosis of Parkinson disease is not always clear-cut. For example, shaking can be secondary to a dopamine receptor-blocking medication, to anxiety, or to essential tremor; rigidity and slowness may be due to arthritis; and postural instability can result from a neuropathy. Moreover, other neurodegenerative parkinsonian disorders may respond to levodopa (at least initially) and may present with levodopa-induced dyskinesias. Robust response to levodopa and the occurrence of dyskinesias are two additional features that strongly suggest the diagnosis of Parkinson disease.

Supporting parkinsonian features include stooped posture, masked facies, micrographia (small handwriting), drooling, speech changes (eg, hypophonia or soft speech, stuttering, slurring, monotonic speech), and a shuffling, festinating gait (quick short steps as if falling forward).

PARKINSON MIMICS

Parkinsonism is a broader term than Parkinson disease or idiopathic Parkinson disease. It is characterized by akinetic rigidity and impaired motor activity that leads to reduced function and falls; behavioral changes also may occur.

In the United States, Parkinson disease is the most common cause of parkinsonism. Other nonneurodegenerative causes are drug-induced parkinsonism (due to dopamine receptor antagonists such as antipsychotic or antiemetic drugs), stroke (in the basal ganglia or frontal lobe), and normal-pressure hydrocephalus (causing lower-body parkinsonism). Mimics of parkinsonism include essential tremor and psychogenic parkinsonism.

Parkinsonism can also be caused by Parkinson-plus disorders, ie, neurodegenerative conditions characterized by parkinsonism along with additional signs and symptoms, as listed below. Parkinson-plus disorders include progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and Lewy body disease.

Clinical features that suggest a diagnosis other than Parkinson disease include¹:

• Poor response to adequate dosages of levodopa
• Early onset of postural instability and falls
• Axial rigidity (eg, stiff neck) more than appendicular rigidity
• Early dementia
• Supranuclear gaze palsy
• Unusual movements besides tremor, eg, limb dystonia, myoclonus, limb levitation or alien limb syndrome
• Profound autonomic dysfunction
• Psychotic symptoms before taking levodopa or dopaminergic medication.

The precise diagnosis of Parkinson-plus disorders is not critical, as the treatment is generally the same for all of them: ie, levodopa (if it shows some efficacy and is well tolerated), with additional symptomatic treatment for features such as depression, cognitive impairment, and autonomic dysfunction, and supportive therapy including physical, occupational, speech, and swallowing therapy.

IMAGING MAY ASSIST IN THE DIAGNOSIS

Dopamine transporter single-photon emission computed tomography (SPECT) is a functional imaging technique that supposedly reflects dopamine uptake by surviving presynaptic dopaminergic neurons in the striate bodies of the basal ganglia. Normal uptake shows distinct cashew-shaped enhancement bilaterally. In Parkinson disease, the enhanced areas are smaller and asymmetric, first with diminution of the tail (representing the putamen), then later involving the head (representing the caudate) along with the other striate bodies (Figure 1).

Dopamine transporter SPECT does not distinguish one neurodegenerative parkinsonian disorder from another. Therefore, it should not be used to distinguish Parkinson disease from other Parkinson-plus syndromes. But it does distinguish neurodegenerative parkinsonian disorders from nonneurodegenerative conditions and mimics, which have a normal result on dopamine transporter SPECT (Table 1).

SLOWING DISEASE PROGRESSION

Current treatments for Parkinson disease can significantly improve symptoms but, unfortunately, do not cure the disease or slow its progression. Testing whether agents modify the disease course is particularly difficult with Parkinson disease, because it affects individuals differently, has a wide spectrum of symptoms, has a long time course, and lacks definitive markers to monitor progression. Some agents have shown promise:

Caffeine. People who drink coffee are less likely to develop Parkinson disease, with the risk declining with the number of cups per day.² For those who have the disease, drinking coffee is associated with reduced symptoms.

Exercise improves Parkinson disease and may prevent it, and some studies suggest that it can delay its progression.³ Exercise has been shown in an animal model to reduce the vulnerability of dopamine neurons to the toxic agent 6-hydroxydopamine.⁴ Functional magnetic resonance imaging studies have shown blood flow patterns before and after exercise that are similar to those seen in patients with and without Parkinson medication.³

Rasagiline, a monoamine oxidase B (MAO-B) inhibitor used for symptomatic treatment of Parkinson disease, had conflicting results in a neuroprotective clinical trial. Patients who received rasagiline 1 mg daily—but not those who received 2 mg daily—at the beginning of the trial had better Parkinson motor scores compared with patients who received rasagiline 9 months later.⁵

Inosine is a urate precursor that elevates urate levels in serum and the central nervous system. For unknown reasons, patients with Parkinson disease tend to have a low uric acid level, and higher levels are associated with milder disease. It is hoped that raising the uric acid level to a “pre-gout level” may slow the progression of Parkinson disease.

Isradipine, a calcium channel blocker, was found in an epidemiologic study of elderly patients to be associated with reduced likelihood of developing Parkinson disease.⁶ The drug is now undergoing clinical trials.

Smoking. Although cigarette smokers have long been recognized as having a very low risk of developing Parkinson disease, smoking is not recommended.

Agents found ineffective. Agents that have been tested and found ineffective in modifying the course of Parkinson disease include vitamin E, coenzyme Q10, riluzole, GPI-1485, pramipexole, cogane, CEP-1347, TCH-346, and creatine.

NOT JUST DOPAMINE—OR TREMORS

Dopamine deficiency is central to the current understanding of the pathogenesis of Parkinson disease and the focus of treatment efforts, but if dopamine deficiency were the only problem, replacing it should completely ameliorate all parkinsonian features. Other neurotransmitters also play roles: norepinephrine is implicated in orthostatic symptoms and apathy, acetylcholine in cognitive behaviors, glutamate in dyskinesias, and serotonin in depression, anxiety, and sleep abnormalities.

The most recognized area of involvement in the brain has traditionally been the substantia nigra in the midbrain. However, current thinking is that the disease starts lower in the caudal area of the brainstem (along with the olfactory tubercle), moves through the pons to the midbrain, then spreads across the cerebrum with extensive neocortical involvement.

Early premotor indicators are now recognized to occur 15 to 20 years before a tremor appears. The first signs are often hyposmia (diminished sense of smell, reflecting involvement of the olfactory tubercle) and constipation (reflecting involvement of the medulla and the vagus nucleus). With pons involvement, the patient can develop rapid eye movement sleep behavior disorder, depression, or anxiety. Only then does the disease spread to the midbrain and cause resting tremor, rigidity, and bradykinesia.⁷

Identifying the preclinical stages and starting disease-modifying treatments before the onset of motor symptoms may one day prove important, but at this point, the premotor symptoms (anosmia, constipation, depression) are too nonspecific to be useful, and such treatments have not yet been identified.

TREATMENT: LEVODOPA STILL PRIMARY

When gait problems develop, treatment should be startedWhen to start drug treatment depends primarily on how much the symptoms bother the patient. Regardless of the clinician’s (or patient’s) belief in the benefits of delaying symptomatic treatment, it is universally considered necessary to start medication when gait problems develop because of the danger of a fall and resulting disability.

Carbidopa-levodopa combination therapy remains the most effective treatment; if it is not effective, another diagnosis may need to be considered. Carbidopa-levodopa improves tremor, rigidity, and bradykinesia, particularly in the early stages of Parkinson disease. It is well tolerated, has rapid onset, reduces the risk of death, and is the least expensive of the medications for Parkinson disease.

Immediate-release and continued-release formulations are available, as well as one that dissolves rapidly on the tongue and can be taken without water. An oral extended-release carbidopa-levodopa formulation (Rytary) was approved by the FDA in January 2015. Tablets are filled with drug-containing microbeads that dissolve at different rates to achieve therapeutic levodopa levels as quickly as the immediate-release formulation and maintain them for an extended time.⁸

The development of dyskinesias is the major psychological drawback of levodopa, occurring in 80% of patients after 5 to 10 years of treatment. Although many patients fear this side effect, most patients who develop it find it preferable to the rigidity and bradykinesia of Parkinson disease. In most cases, bothersome dyskinesias can be controlled by adjusting medications.^9,10

Dopamine agonists include pramipexole, ropinirole, and rotigotine. They are available in generic form as three-times-daily dosing; once-daily dosing is also available, but not as a generic formulation. Dopamine agonists have the advantage of potentially improving depression and delaying the onset of dyskinesias.

However, dopamine agonists have a number of disadvantages compared with levodopa: they have a longer titration period, are less effective, and are less well tolerated, especially in the elderly. Side effects occur more frequently than with levodopa and include general and peripheral edema, hallucinations, nausea, lightheadedness, and sleepiness.^11,12 These drugs are also associated with “sleep attacks” (sudden falling asleep while active, such as while driving or eating) and with compulsive and impulsive behaviors such as hypersexuality, buying, binge eating, and gambling. Although these behaviors occur in fewer than 10% of patients, they can be devastating, leading to marital, financial, and legal problems. A bothersome clinical state termed dopamine agonist withdrawal syndrome is characterized by anxiety, depression, jitteriness, and palpitations when dopamine agonists are tapered or discontinued because of a side effect.¹³

MAO-B inhibitors delay the breakdown of dopamine, allowing it to “stay” in the brain for a longer period of time. Rasagiline for early monotherapy has the advantages of once-daily dosing, no titration, and excellent tolerability, even in the elderly. Potential drug interactions should be considered when using this drug. Early warnings about interactions with tyramine-rich foods were lifted after trials showed that this was not a problem.¹⁴

Amantadine is an N-methyl-d-aspartate (NMDA) receptor antagonist often used in early Parkinson disease and for treatment of dyskinesias and fatigue. It is the only drug that is intrinsically antidyskinetic and also improves Parkinson symptoms.¹⁵ Side effects include leg swelling, livedo reticularis, and neuropsychiatric and anticholinergic effects.

Anticholinergic agents (eg, trihexyphenidyl) improve tremor but are not as useful for bradykinesia or rigidity, and often have anticholinergic effects such as mental dullness, dry mouth, dry eye, and urinary hesitancy, especially in the elderly, so they have a limited role in Parkinson treatment.

MOTOR COMPLICATIONS: FLUCTUATIONS AND DYSKINESIAS

Motor fluctuations are changes between the akinetic and mobile phases of Parkinson disease, or the off-periods and on-periods of drug treatment. A patient who is “off” is generally rigid and feels that the medication is not working. A patient who is “on” feels loose and mobile and that the medication is working. Variants of motor fluctuations include:

• End-of-dose deterioration
• Delayed onset of response (more than half an hour after taking medication)
• Drug-resistant offs—medication has become ineffective
• Random oscillation—on-off phenomenon
• Freezing—unpredictable inability to start or finish a movement.

Dyskinesias are abnormal involuntary movements such as writhing and twisting. They are associated with dopaminergic therapy at peak dose, when the drug starts to turn on or wear off (termed diphasic dyskinesias).¹⁶

The storage hypothesis provides a plausible explanation for the development of motor complications as the disease progresses. Although the half-life of levodopa is only 60 to 90 minutes, it is effective in early disease when given three times a day. It is believed that at this stage of the disease, enough dopaminergic neurons survive to “store” dopamine and release it as needed. As the disease progresses and dopaminergic neurons die, storage capacity diminishes, and the clinical effect slowly starts to approximate the pharmacokinetic profile of the drug. Upon taking the medication, the patient gets a surge of drug, causing dyskinesias, followed later by rigidity as the effect wears off since there are fewer surviving dopaminergic cells to store dopamine.

MANAGING DYSKINESIAS

Patients with dyskinesias should first be asked if they are bothered by them; not all patients are troubled by dyskinesias. If the movements only bother others (eg, family members), then education is often the only treatment needed. If the patient is uncomfortable, the following measures can be tried:

• Taking lower, more frequent doses of levodopa (however, risk of wearing off becomes a problem)
• Adding a dopamine agonist or MAO-B inhibitor while lowering the levodopa dose (however, MAO-B inhibitors pose a risk of side effects in elderly patients)
• Adding clozapine (periodic laboratory testing is required to monitor blood levels and liver and kidney function)
• Adding amantadine (however, this poses a risk of cognitive side effects).

Deep-brain-stimulation surgery is appropriate for select patients who are generally physically healthy, cognitively intact, and emotionally stable, with a strong family support system, but who are bothered by symptoms of parkinsonism (such as tremors), motor fluctuations, or dyskinesias.¹⁷

Infusion pump. In January 2015, the FDA approved a new system that continuously delivers levodopa-carbidopa in a 4:1 ratio in gel suspension for 16 hours directly into the small intestine, minimizing motor fluctuations. The patient changes the cartridge daily and turns it off at bedtime.

*Dr. Fernandez has received research support from AbbVie, Acadia, Auspex, Biotie Therapies, Civitas, Kyowa/ProStrakan, Michael J. Fox Foundation, Movement Disorders Society, NIH/NINDS, Parkinson Study Group, Rhythm, Synosia, and Teva. He also has received honoraria from Carling Communications, International Parkinson and Movement Disorders Society, The Ohio State University, and PRIME Education, Inc as a speaker in CME events. He has received honoraria from Biogen, GE Health Care, Lundbeck, Merz Pharmaceuticals, and Pfizer as a consultant. He has received royalty payments from Demos Publishing for serving as a book author/editor. Cleveland Clinic has contracts with AbbVie and Merz Pharmaceuticals for Dr. Fernandez’s role as a member of the Global Steering Committee for LCIG studies and as a consultant or speaker, and as Head Principal Investigator for the Xeomin Registry Study. Dr. Fernandez has received a stipend from International Parkinson and Movement Disorders Society for serving as medical editor of the Movement Disorders Society website.
 

This has been a boom year for Parkinson disease, with the US Food and Drug Administration (FDA) approving two new therapies, and with others in the pipeline.

This article details clinical signs of Parkinson disease, discusses functional imaging, provides an update on current thinking on disease pathogenesis, and gives an overview of managing parkinsonian symptoms and dyskinesias.

DIAGNOSIS REMAINS CLINICAL

Although a better understanding of Parkinson disease has been gained in recent years, with the recognition of several premotor features and potential biomarkers, its diagnosis is still primarily based on clinical motor findings. The four cardinal motor features have the mnemonic TRAP:

• Tremor at rest can be subtle, involving just the thumb, best observed when the patient is sitting with the hand resting on the lap; or it can be obvious, involving the entire hand, arm, feet, lips, and chin.
• Rigidity can be felt rather than seen, by slowly passively rotating the patient’s wrist or elbow and feeling resistance. The right and left sides often differ.
• Akinesia or bradykinesia (slowness or lack of movement) can be observed by having the patient walk down a hallway. One may observe reduced arm swing and hesitation in initiating movement.
• Postural instability usually develops later rather than sooner in the disease progression. The patient may need to hold onto someone to maintain balance when getting up or walking.

At least two features must be present to make the diagnosis of parkinsonism. One feature must be tremor or rigidity.

The TRAP features of Parkinson disease:
• Tremor
• Rigidity
• Akinesia
• Postural instabilityAlthough the criteria for parkinsonism appear simple, the diagnosis of Parkinson disease is not always clear-cut. For example, shaking can be secondary to a dopamine receptor-blocking medication, to anxiety, or to essential tremor; rigidity and slowness may be due to arthritis; and postural instability can result from a neuropathy. Moreover, other neurodegenerative parkinsonian disorders may respond to levodopa (at least initially) and may present with levodopa-induced dyskinesias. Robust response to levodopa and the occurrence of dyskinesias are two additional features that strongly suggest the diagnosis of Parkinson disease.

Supporting parkinsonian features include stooped posture, masked facies, micrographia (small handwriting), drooling, speech changes (eg, hypophonia or soft speech, stuttering, slurring, monotonic speech), and a shuffling, festinating gait (quick short steps as if falling forward).

PARKINSON MIMICS

Parkinsonism is a broader term than Parkinson disease or idiopathic Parkinson disease. It is characterized by akinetic rigidity and impaired motor activity that leads to reduced function and falls; behavioral changes also may occur.

In the United States, Parkinson disease is the most common cause of parkinsonism. Other nonneurodegenerative causes are drug-induced parkinsonism (due to dopamine receptor antagonists such as antipsychotic or antiemetic drugs), stroke (in the basal ganglia or frontal lobe), and normal-pressure hydrocephalus (causing lower-body parkinsonism). Mimics of parkinsonism include essential tremor and psychogenic parkinsonism.

Parkinsonism can also be caused by Parkinson-plus disorders, ie, neurodegenerative conditions characterized by parkinsonism along with additional signs and symptoms, as listed below. Parkinson-plus disorders include progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and Lewy body disease.

Clinical features that suggest a diagnosis other than Parkinson disease include¹:

• Poor response to adequate dosages of levodopa
• Early onset of postural instability and falls
• Axial rigidity (eg, stiff neck) more than appendicular rigidity
• Early dementia
• Supranuclear gaze palsy
• Unusual movements besides tremor, eg, limb dystonia, myoclonus, limb levitation or alien limb syndrome
• Profound autonomic dysfunction
• Psychotic symptoms before taking levodopa or dopaminergic medication.

The precise diagnosis of Parkinson-plus disorders is not critical, as the treatment is generally the same for all of them: ie, levodopa (if it shows some efficacy and is well tolerated), with additional symptomatic treatment for features such as depression, cognitive impairment, and autonomic dysfunction, and supportive therapy including physical, occupational, speech, and swallowing therapy.

IMAGING MAY ASSIST IN THE DIAGNOSIS

Dopamine transporter single-photon emission computed tomography (SPECT) is a functional imaging technique that supposedly reflects dopamine uptake by surviving presynaptic dopaminergic neurons in the striate bodies of the basal ganglia. Normal uptake shows distinct cashew-shaped enhancement bilaterally. In Parkinson disease, the enhanced areas are smaller and asymmetric, first with diminution of the tail (representing the putamen), then later involving the head (representing the caudate) along with the other striate bodies (Figure 1).

Dopamine transporter SPECT does not distinguish one neurodegenerative parkinsonian disorder from another. Therefore, it should not be used to distinguish Parkinson disease from other Parkinson-plus syndromes. But it does distinguish neurodegenerative parkinsonian disorders from nonneurodegenerative conditions and mimics, which have a normal result on dopamine transporter SPECT (Table 1).

SLOWING DISEASE PROGRESSION

Current treatments for Parkinson disease can significantly improve symptoms but, unfortunately, do not cure the disease or slow its progression. Testing whether agents modify the disease course is particularly difficult with Parkinson disease, because it affects individuals differently, has a wide spectrum of symptoms, has a long time course, and lacks definitive markers to monitor progression. Some agents have shown promise:

Caffeine. People who drink coffee are less likely to develop Parkinson disease, with the risk declining with the number of cups per day.² For those who have the disease, drinking coffee is associated with reduced symptoms.

Exercise improves Parkinson disease and may prevent it, and some studies suggest that it can delay its progression.³ Exercise has been shown in an animal model to reduce the vulnerability of dopamine neurons to the toxic agent 6-hydroxydopamine.⁴ Functional magnetic resonance imaging studies have shown blood flow patterns before and after exercise that are similar to those seen in patients with and without Parkinson medication.³

Rasagiline, a monoamine oxidase B (MAO-B) inhibitor used for symptomatic treatment of Parkinson disease, had conflicting results in a neuroprotective clinical trial. Patients who received rasagiline 1 mg daily—but not those who received 2 mg daily—at the beginning of the trial had better Parkinson motor scores compared with patients who received rasagiline 9 months later.⁵

Inosine is a urate precursor that elevates urate levels in serum and the central nervous system. For unknown reasons, patients with Parkinson disease tend to have a low uric acid level, and higher levels are associated with milder disease. It is hoped that raising the uric acid level to a “pre-gout level” may slow the progression of Parkinson disease.

Isradipine, a calcium channel blocker, was found in an epidemiologic study of elderly patients to be associated with reduced likelihood of developing Parkinson disease.⁶ The drug is now undergoing clinical trials.

Smoking. Although cigarette smokers have long been recognized as having a very low risk of developing Parkinson disease, smoking is not recommended.

Agents found ineffective. Agents that have been tested and found ineffective in modifying the course of Parkinson disease include vitamin E, coenzyme Q10, riluzole, GPI-1485, pramipexole, cogane, CEP-1347, TCH-346, and creatine.

NOT JUST DOPAMINE—OR TREMORS

Dopamine deficiency is central to the current understanding of the pathogenesis of Parkinson disease and the focus of treatment efforts, but if dopamine deficiency were the only problem, replacing it should completely ameliorate all parkinsonian features. Other neurotransmitters also play roles: norepinephrine is implicated in orthostatic symptoms and apathy, acetylcholine in cognitive behaviors, glutamate in dyskinesias, and serotonin in depression, anxiety, and sleep abnormalities.

The most recognized area of involvement in the brain has traditionally been the substantia nigra in the midbrain. However, current thinking is that the disease starts lower in the caudal area of the brainstem (along with the olfactory tubercle), moves through the pons to the midbrain, then spreads across the cerebrum with extensive neocortical involvement.

Early premotor indicators are now recognized to occur 15 to 20 years before a tremor appears. The first signs are often hyposmia (diminished sense of smell, reflecting involvement of the olfactory tubercle) and constipation (reflecting involvement of the medulla and the vagus nucleus). With pons involvement, the patient can develop rapid eye movement sleep behavior disorder, depression, or anxiety. Only then does the disease spread to the midbrain and cause resting tremor, rigidity, and bradykinesia.⁷

Identifying the preclinical stages and starting disease-modifying treatments before the onset of motor symptoms may one day prove important, but at this point, the premotor symptoms (anosmia, constipation, depression) are too nonspecific to be useful, and such treatments have not yet been identified.

TREATMENT: LEVODOPA STILL PRIMARY

When gait problems develop, treatment should be startedWhen to start drug treatment depends primarily on how much the symptoms bother the patient. Regardless of the clinician’s (or patient’s) belief in the benefits of delaying symptomatic treatment, it is universally considered necessary to start medication when gait problems develop because of the danger of a fall and resulting disability.

Carbidopa-levodopa combination therapy remains the most effective treatment; if it is not effective, another diagnosis may need to be considered. Carbidopa-levodopa improves tremor, rigidity, and bradykinesia, particularly in the early stages of Parkinson disease. It is well tolerated, has rapid onset, reduces the risk of death, and is the least expensive of the medications for Parkinson disease.

Immediate-release and continued-release formulations are available, as well as one that dissolves rapidly on the tongue and can be taken without water. An oral extended-release carbidopa-levodopa formulation (Rytary) was approved by the FDA in January 2015. Tablets are filled with drug-containing microbeads that dissolve at different rates to achieve therapeutic levodopa levels as quickly as the immediate-release formulation and maintain them for an extended time.⁸

The development of dyskinesias is the major psychological drawback of levodopa, occurring in 80% of patients after 5 to 10 years of treatment. Although many patients fear this side effect, most patients who develop it find it preferable to the rigidity and bradykinesia of Parkinson disease. In most cases, bothersome dyskinesias can be controlled by adjusting medications.^9,10

Dopamine agonists include pramipexole, ropinirole, and rotigotine. They are available in generic form as three-times-daily dosing; once-daily dosing is also available, but not as a generic formulation. Dopamine agonists have the advantage of potentially improving depression and delaying the onset of dyskinesias.

However, dopamine agonists have a number of disadvantages compared with levodopa: they have a longer titration period, are less effective, and are less well tolerated, especially in the elderly. Side effects occur more frequently than with levodopa and include general and peripheral edema, hallucinations, nausea, lightheadedness, and sleepiness.^11,12 These drugs are also associated with “sleep attacks” (sudden falling asleep while active, such as while driving or eating) and with compulsive and impulsive behaviors such as hypersexuality, buying, binge eating, and gambling. Although these behaviors occur in fewer than 10% of patients, they can be devastating, leading to marital, financial, and legal problems. A bothersome clinical state termed dopamine agonist withdrawal syndrome is characterized by anxiety, depression, jitteriness, and palpitations when dopamine agonists are tapered or discontinued because of a side effect.¹³

MAO-B inhibitors delay the breakdown of dopamine, allowing it to “stay” in the brain for a longer period of time. Rasagiline for early monotherapy has the advantages of once-daily dosing, no titration, and excellent tolerability, even in the elderly. Potential drug interactions should be considered when using this drug. Early warnings about interactions with tyramine-rich foods were lifted after trials showed that this was not a problem.¹⁴

Amantadine is an N-methyl-d-aspartate (NMDA) receptor antagonist often used in early Parkinson disease and for treatment of dyskinesias and fatigue. It is the only drug that is intrinsically antidyskinetic and also improves Parkinson symptoms.¹⁵ Side effects include leg swelling, livedo reticularis, and neuropsychiatric and anticholinergic effects.

Anticholinergic agents (eg, trihexyphenidyl) improve tremor but are not as useful for bradykinesia or rigidity, and often have anticholinergic effects such as mental dullness, dry mouth, dry eye, and urinary hesitancy, especially in the elderly, so they have a limited role in Parkinson treatment.

MOTOR COMPLICATIONS: FLUCTUATIONS AND DYSKINESIAS

Motor fluctuations are changes between the akinetic and mobile phases of Parkinson disease, or the off-periods and on-periods of drug treatment. A patient who is “off” is generally rigid and feels that the medication is not working. A patient who is “on” feels loose and mobile and that the medication is working. Variants of motor fluctuations include:

• End-of-dose deterioration
• Delayed onset of response (more than half an hour after taking medication)
• Drug-resistant offs—medication has become ineffective
• Random oscillation—on-off phenomenon
• Freezing—unpredictable inability to start or finish a movement.

Dyskinesias are abnormal involuntary movements such as writhing and twisting. They are associated with dopaminergic therapy at peak dose, when the drug starts to turn on or wear off (termed diphasic dyskinesias).¹⁶

The storage hypothesis provides a plausible explanation for the development of motor complications as the disease progresses. Although the half-life of levodopa is only 60 to 90 minutes, it is effective in early disease when given three times a day. It is believed that at this stage of the disease, enough dopaminergic neurons survive to “store” dopamine and release it as needed. As the disease progresses and dopaminergic neurons die, storage capacity diminishes, and the clinical effect slowly starts to approximate the pharmacokinetic profile of the drug. Upon taking the medication, the patient gets a surge of drug, causing dyskinesias, followed later by rigidity as the effect wears off since there are fewer surviving dopaminergic cells to store dopamine.

MANAGING DYSKINESIAS

Patients with dyskinesias should first be asked if they are bothered by them; not all patients are troubled by dyskinesias. If the movements only bother others (eg, family members), then education is often the only treatment needed. If the patient is uncomfortable, the following measures can be tried:

• Taking lower, more frequent doses of levodopa (however, risk of wearing off becomes a problem)
• Adding a dopamine agonist or MAO-B inhibitor while lowering the levodopa dose (however, MAO-B inhibitors pose a risk of side effects in elderly patients)
• Adding clozapine (periodic laboratory testing is required to monitor blood levels and liver and kidney function)
• Adding amantadine (however, this poses a risk of cognitive side effects).

Deep-brain-stimulation surgery is appropriate for select patients who are generally physically healthy, cognitively intact, and emotionally stable, with a strong family support system, but who are bothered by symptoms of parkinsonism (such as tremors), motor fluctuations, or dyskinesias.¹⁷

Infusion pump. In January 2015, the FDA approved a new system that continuously delivers levodopa-carbidopa in a 4:1 ratio in gel suspension for 16 hours directly into the small intestine, minimizing motor fluctuations. The patient changes the cartridge daily and turns it off at bedtime.

*Dr. Fernandez has received research support from AbbVie, Acadia, Auspex, Biotie Therapies, Civitas, Kyowa/ProStrakan, Michael J. Fox Foundation, Movement Disorders Society, NIH/NINDS, Parkinson Study Group, Rhythm, Synosia, and Teva. He also has received honoraria from Carling Communications, International Parkinson and Movement Disorders Society, The Ohio State University, and PRIME Education, Inc as a speaker in CME events. He has received honoraria from Biogen, GE Health Care, Lundbeck, Merz Pharmaceuticals, and Pfizer as a consultant. He has received royalty payments from Demos Publishing for serving as a book author/editor. Cleveland Clinic has contracts with AbbVie and Merz Pharmaceuticals for Dr. Fernandez’s role as a member of the Global Steering Committee for LCIG studies and as a consultant or speaker, and as Head Principal Investigator for the Xeomin Registry Study. Dr. Fernandez has received a stipend from International Parkinson and Movement Disorders Society for serving as medical editor of the Movement Disorders Society website.
 

This has been a boom year for Parkinson disease, with the US Food and Drug Administration (FDA) approving two new therapies, and with others in the pipeline.

This article details clinical signs of Parkinson disease, discusses functional imaging, provides an update on current thinking on disease pathogenesis, and gives an overview of managing parkinsonian symptoms and dyskinesias.

DIAGNOSIS REMAINS CLINICAL

Although a better understanding of Parkinson disease has been gained in recent years, with the recognition of several premotor features and potential biomarkers, its diagnosis is still primarily based on clinical motor findings. The four cardinal motor features have the mnemonic TRAP:

• Tremor at rest can be subtle, involving just the thumb, best observed when the patient is sitting with the hand resting on the lap; or it can be obvious, involving the entire hand, arm, feet, lips, and chin.
• Rigidity can be felt rather than seen, by slowly passively rotating the patient’s wrist or elbow and feeling resistance. The right and left sides often differ.
• Akinesia or bradykinesia (slowness or lack of movement) can be observed by having the patient walk down a hallway. One may observe reduced arm swing and hesitation in initiating movement.
• Postural instability usually develops later rather than sooner in the disease progression. The patient may need to hold onto someone to maintain balance when getting up or walking.

At least two features must be present to make the diagnosis of parkinsonism. One feature must be tremor or rigidity.

The TRAP features of Parkinson disease:
• Tremor
• Rigidity
• Akinesia
• Postural instabilityAlthough the criteria for parkinsonism appear simple, the diagnosis of Parkinson disease is not always clear-cut. For example, shaking can be secondary to a dopamine receptor-blocking medication, to anxiety, or to essential tremor; rigidity and slowness may be due to arthritis; and postural instability can result from a neuropathy. Moreover, other neurodegenerative parkinsonian disorders may respond to levodopa (at least initially) and may present with levodopa-induced dyskinesias. Robust response to levodopa and the occurrence of dyskinesias are two additional features that strongly suggest the diagnosis of Parkinson disease.

Supporting parkinsonian features include stooped posture, masked facies, micrographia (small handwriting), drooling, speech changes (eg, hypophonia or soft speech, stuttering, slurring, monotonic speech), and a shuffling, festinating gait (quick short steps as if falling forward).

PARKINSON MIMICS

Parkinsonism is a broader term than Parkinson disease or idiopathic Parkinson disease. It is characterized by akinetic rigidity and impaired motor activity that leads to reduced function and falls; behavioral changes also may occur.

In the United States, Parkinson disease is the most common cause of parkinsonism. Other nonneurodegenerative causes are drug-induced parkinsonism (due to dopamine receptor antagonists such as antipsychotic or antiemetic drugs), stroke (in the basal ganglia or frontal lobe), and normal-pressure hydrocephalus (causing lower-body parkinsonism). Mimics of parkinsonism include essential tremor and psychogenic parkinsonism.

Parkinsonism can also be caused by Parkinson-plus disorders, ie, neurodegenerative conditions characterized by parkinsonism along with additional signs and symptoms, as listed below. Parkinson-plus disorders include progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and Lewy body disease.

Clinical features that suggest a diagnosis other than Parkinson disease include¹:

• Poor response to adequate dosages of levodopa
• Early onset of postural instability and falls
• Axial rigidity (eg, stiff neck) more than appendicular rigidity
• Early dementia
• Supranuclear gaze palsy
• Unusual movements besides tremor, eg, limb dystonia, myoclonus, limb levitation or alien limb syndrome
• Profound autonomic dysfunction
• Psychotic symptoms before taking levodopa or dopaminergic medication.

The precise diagnosis of Parkinson-plus disorders is not critical, as the treatment is generally the same for all of them: ie, levodopa (if it shows some efficacy and is well tolerated), with additional symptomatic treatment for features such as depression, cognitive impairment, and autonomic dysfunction, and supportive therapy including physical, occupational, speech, and swallowing therapy.

IMAGING MAY ASSIST IN THE DIAGNOSIS

Dopamine transporter single-photon emission computed tomography (SPECT) is a functional imaging technique that supposedly reflects dopamine uptake by surviving presynaptic dopaminergic neurons in the striate bodies of the basal ganglia. Normal uptake shows distinct cashew-shaped enhancement bilaterally. In Parkinson disease, the enhanced areas are smaller and asymmetric, first with diminution of the tail (representing the putamen), then later involving the head (representing the caudate) along with the other striate bodies (Figure 1).

Dopamine transporter SPECT does not distinguish one neurodegenerative parkinsonian disorder from another. Therefore, it should not be used to distinguish Parkinson disease from other Parkinson-plus syndromes. But it does distinguish neurodegenerative parkinsonian disorders from nonneurodegenerative conditions and mimics, which have a normal result on dopamine transporter SPECT (Table 1).

SLOWING DISEASE PROGRESSION

Current treatments for Parkinson disease can significantly improve symptoms but, unfortunately, do not cure the disease or slow its progression. Testing whether agents modify the disease course is particularly difficult with Parkinson disease, because it affects individuals differently, has a wide spectrum of symptoms, has a long time course, and lacks definitive markers to monitor progression. Some agents have shown promise:

Caffeine. People who drink coffee are less likely to develop Parkinson disease, with the risk declining with the number of cups per day.² For those who have the disease, drinking coffee is associated with reduced symptoms.

Exercise improves Parkinson disease and may prevent it, and some studies suggest that it can delay its progression.³ Exercise has been shown in an animal model to reduce the vulnerability of dopamine neurons to the toxic agent 6-hydroxydopamine.⁴ Functional magnetic resonance imaging studies have shown blood flow patterns before and after exercise that are similar to those seen in patients with and without Parkinson medication.³

Rasagiline, a monoamine oxidase B (MAO-B) inhibitor used for symptomatic treatment of Parkinson disease, had conflicting results in a neuroprotective clinical trial. Patients who received rasagiline 1 mg daily—but not those who received 2 mg daily—at the beginning of the trial had better Parkinson motor scores compared with patients who received rasagiline 9 months later.⁵

Inosine is a urate precursor that elevates urate levels in serum and the central nervous system. For unknown reasons, patients with Parkinson disease tend to have a low uric acid level, and higher levels are associated with milder disease. It is hoped that raising the uric acid level to a “pre-gout level” may slow the progression of Parkinson disease.

Isradipine, a calcium channel blocker, was found in an epidemiologic study of elderly patients to be associated with reduced likelihood of developing Parkinson disease.⁶ The drug is now undergoing clinical trials.

Smoking. Although cigarette smokers have long been recognized as having a very low risk of developing Parkinson disease, smoking is not recommended.

Agents found ineffective. Agents that have been tested and found ineffective in modifying the course of Parkinson disease include vitamin E, coenzyme Q10, riluzole, GPI-1485, pramipexole, cogane, CEP-1347, TCH-346, and creatine.

NOT JUST DOPAMINE—OR TREMORS

Dopamine deficiency is central to the current understanding of the pathogenesis of Parkinson disease and the focus of treatment efforts, but if dopamine deficiency were the only problem, replacing it should completely ameliorate all parkinsonian features. Other neurotransmitters also play roles: norepinephrine is implicated in orthostatic symptoms and apathy, acetylcholine in cognitive behaviors, glutamate in dyskinesias, and serotonin in depression, anxiety, and sleep abnormalities.

The most recognized area of involvement in the brain has traditionally been the substantia nigra in the midbrain. However, current thinking is that the disease starts lower in the caudal area of the brainstem (along with the olfactory tubercle), moves through the pons to the midbrain, then spreads across the cerebrum with extensive neocortical involvement.

Early premotor indicators are now recognized to occur 15 to 20 years before a tremor appears. The first signs are often hyposmia (diminished sense of smell, reflecting involvement of the olfactory tubercle) and constipation (reflecting involvement of the medulla and the vagus nucleus). With pons involvement, the patient can develop rapid eye movement sleep behavior disorder, depression, or anxiety. Only then does the disease spread to the midbrain and cause resting tremor, rigidity, and bradykinesia.⁷

Identifying the preclinical stages and starting disease-modifying treatments before the onset of motor symptoms may one day prove important, but at this point, the premotor symptoms (anosmia, constipation, depression) are too nonspecific to be useful, and such treatments have not yet been identified.

TREATMENT: LEVODOPA STILL PRIMARY

When gait problems develop, treatment should be startedWhen to start drug treatment depends primarily on how much the symptoms bother the patient. Regardless of the clinician’s (or patient’s) belief in the benefits of delaying symptomatic treatment, it is universally considered necessary to start medication when gait problems develop because of the danger of a fall and resulting disability.

Carbidopa-levodopa combination therapy remains the most effective treatment; if it is not effective, another diagnosis may need to be considered. Carbidopa-levodopa improves tremor, rigidity, and bradykinesia, particularly in the early stages of Parkinson disease. It is well tolerated, has rapid onset, reduces the risk of death, and is the least expensive of the medications for Parkinson disease.

Immediate-release and continued-release formulations are available, as well as one that dissolves rapidly on the tongue and can be taken without water. An oral extended-release carbidopa-levodopa formulation (Rytary) was approved by the FDA in January 2015. Tablets are filled with drug-containing microbeads that dissolve at different rates to achieve therapeutic levodopa levels as quickly as the immediate-release formulation and maintain them for an extended time.⁸

The development of dyskinesias is the major psychological drawback of levodopa, occurring in 80% of patients after 5 to 10 years of treatment. Although many patients fear this side effect, most patients who develop it find it preferable to the rigidity and bradykinesia of Parkinson disease. In most cases, bothersome dyskinesias can be controlled by adjusting medications.^9,10

Dopamine agonists include pramipexole, ropinirole, and rotigotine. They are available in generic form as three-times-daily dosing; once-daily dosing is also available, but not as a generic formulation. Dopamine agonists have the advantage of potentially improving depression and delaying the onset of dyskinesias.

However, dopamine agonists have a number of disadvantages compared with levodopa: they have a longer titration period, are less effective, and are less well tolerated, especially in the elderly. Side effects occur more frequently than with levodopa and include general and peripheral edema, hallucinations, nausea, lightheadedness, and sleepiness.^11,12 These drugs are also associated with “sleep attacks” (sudden falling asleep while active, such as while driving or eating) and with compulsive and impulsive behaviors such as hypersexuality, buying, binge eating, and gambling. Although these behaviors occur in fewer than 10% of patients, they can be devastating, leading to marital, financial, and legal problems. A bothersome clinical state termed dopamine agonist withdrawal syndrome is characterized by anxiety, depression, jitteriness, and palpitations when dopamine agonists are tapered or discontinued because of a side effect.¹³

MAO-B inhibitors delay the breakdown of dopamine, allowing it to “stay” in the brain for a longer period of time. Rasagiline for early monotherapy has the advantages of once-daily dosing, no titration, and excellent tolerability, even in the elderly. Potential drug interactions should be considered when using this drug. Early warnings about interactions with tyramine-rich foods were lifted after trials showed that this was not a problem.¹⁴

Amantadine is an N-methyl-d-aspartate (NMDA) receptor antagonist often used in early Parkinson disease and for treatment of dyskinesias and fatigue. It is the only drug that is intrinsically antidyskinetic and also improves Parkinson symptoms.¹⁵ Side effects include leg swelling, livedo reticularis, and neuropsychiatric and anticholinergic effects.

Anticholinergic agents (eg, trihexyphenidyl) improve tremor but are not as useful for bradykinesia or rigidity, and often have anticholinergic effects such as mental dullness, dry mouth, dry eye, and urinary hesitancy, especially in the elderly, so they have a limited role in Parkinson treatment.

MOTOR COMPLICATIONS: FLUCTUATIONS AND DYSKINESIAS

Motor fluctuations are changes between the akinetic and mobile phases of Parkinson disease, or the off-periods and on-periods of drug treatment. A patient who is “off” is generally rigid and feels that the medication is not working. A patient who is “on” feels loose and mobile and that the medication is working. Variants of motor fluctuations include:

• End-of-dose deterioration
• Delayed onset of response (more than half an hour after taking medication)
• Drug-resistant offs—medication has become ineffective
• Random oscillation—on-off phenomenon
• Freezing—unpredictable inability to start or finish a movement.

Dyskinesias are abnormal involuntary movements such as writhing and twisting. They are associated with dopaminergic therapy at peak dose, when the drug starts to turn on or wear off (termed diphasic dyskinesias).¹⁶

The storage hypothesis provides a plausible explanation for the development of motor complications as the disease progresses. Although the half-life of levodopa is only 60 to 90 minutes, it is effective in early disease when given three times a day. It is believed that at this stage of the disease, enough dopaminergic neurons survive to “store” dopamine and release it as needed. As the disease progresses and dopaminergic neurons die, storage capacity diminishes, and the clinical effect slowly starts to approximate the pharmacokinetic profile of the drug. Upon taking the medication, the patient gets a surge of drug, causing dyskinesias, followed later by rigidity as the effect wears off since there are fewer surviving dopaminergic cells to store dopamine.

MANAGING DYSKINESIAS

Patients with dyskinesias should first be asked if they are bothered by them; not all patients are troubled by dyskinesias. If the movements only bother others (eg, family members), then education is often the only treatment needed. If the patient is uncomfortable, the following measures can be tried:

• Taking lower, more frequent doses of levodopa (however, risk of wearing off becomes a problem)
• Adding a dopamine agonist or MAO-B inhibitor while lowering the levodopa dose (however, MAO-B inhibitors pose a risk of side effects in elderly patients)
• Adding clozapine (periodic laboratory testing is required to monitor blood levels and liver and kidney function)
• Adding amantadine (however, this poses a risk of cognitive side effects).

Deep-brain-stimulation surgery is appropriate for select patients who are generally physically healthy, cognitively intact, and emotionally stable, with a strong family support system, but who are bothered by symptoms of parkinsonism (such as tremors), motor fluctuations, or dyskinesias.¹⁷

Infusion pump. In January 2015, the FDA approved a new system that continuously delivers levodopa-carbidopa in a 4:1 ratio in gel suspension for 16 hours directly into the small intestine, minimizing motor fluctuations. The patient changes the cartridge daily and turns it off at bedtime.

*Dr. Fernandez has received research support from AbbVie, Acadia, Auspex, Biotie Therapies, Civitas, Kyowa/ProStrakan, Michael J. Fox Foundation, Movement Disorders Society, NIH/NINDS, Parkinson Study Group, Rhythm, Synosia, and Teva. He also has received honoraria from Carling Communications, International Parkinson and Movement Disorders Society, The Ohio State University, and PRIME Education, Inc as a speaker in CME events. He has received honoraria from Biogen, GE Health Care, Lundbeck, Merz Pharmaceuticals, and Pfizer as a consultant. He has received royalty payments from Demos Publishing for serving as a book author/editor. Cleveland Clinic has contracts with AbbVie and Merz Pharmaceuticals for Dr. Fernandez’s role as a member of the Global Steering Committee for LCIG studies and as a consultant or speaker, and as Head Principal Investigator for the Xeomin Registry Study. Dr. Fernandez has received a stipend from International Parkinson and Movement Disorders Society for serving as medical editor of the Movement Disorders Society website.